Peptides that bind to the erythropoietin receptor

ABSTRACT

Peptides of 10 to 40 or more amino acid residues in length and having the sequence X3X4X5GPX6TWX7X8 (SEQ ID NO:252) where each amino acid is indicated by standard one letter abbreviation; X3 is C; X4 is R, H, L, or W; X 5  is M, F, or I; X6 is independently selected from any one of the 20 genetically coded L-amino acids; X7 is D, E, I, L, or V; and X8 is C, which bind and activate the erythropoietin receptor (EPO-R) or otherwise act as an EPO agonist, and methods for their use.

This application is a continuation of Ser. No. 08/484,635, filed Jun. 7,1995, now U.S. Pat. No. 5,773,569, which is a continuation-in-part Ser.No. 08/155,940, filed Nov. 19, 1993, now abandoned, which isincorporated herein reference.

FIELD OF THE INVENTION

The present invention provides, inter alia, peptides and compounds thatbind and activate the erythropoietin receptor (EPO-R) or otherwise actas an EPO agonist. The invention has application in the fields ofbiochemistry and medicinal chemistry and particularly provides EPOagonists for use in the treatment of human disease.

BACKGROUND OF THE INVENTION

Erythropoietin (EPO) is a glycoprotein hormone with 165 amino acids, 4glycosylation sites on amino-acid positions 24, 38, 83, and 126, and amolecular weight of about 34,000. It is initially produced as aprecursor protein with a signal peptide of 23 amino acids. EPO can occurin three forms: α, β, and asialo. The α and β forms differ slightly inthe carbohydrate components, but have the same potency, biologicalactivity, and molecular weight. The asialo form is an α or β form withthe terminal carbohydrate (sialic acid) removed. The DNA sequencesencoding EPO have been reported. See, Lin (1987) U.S. Pat. No.4,703,008, which is incorporated herein by reference.

EPO stimulates mitotic division and the differentiation of erythrocyteprecursor cells and thus ensures the production of erythrocytes. It isproduced in the kidney when hypoxic conditions prevail. DuringEPOinduced differentiation of erythrocyte precursor cells, there isinduction of globin synthesis and increases in the synthesis of the hemecomplex and in the number of ferritin receptors. This make it possiblefor the cell to take on more iron and synthesize functional hemoglobin.Hemoglobin in mature erythrocytes binds oxygen. Thus, the erythrocytesand the hemoglobin contained in them play a key part in supplying thebody with oxygen. The complex processes which have been described areinitiated by the interaction of EPO with an appropriate receptor on thecell surface of the erythrocyte precursor cells. See, e.g., Graber andKrantz (1978) Ann. Rev. Med. 29:51-66.

EPO is present in very low concentrations in plasma when the body is ina healthy state wherein tissues receive sufficient oxygenation from theexisting number of erythrocytes. This normal low concentration is enoughto stimulate replacement of red blood cells which are lost normallythrough aging.

The amount of EPO in the circulation is increased under conditions ofhypoxia when oxygen transport by blood cells in the circulation isreduced. Hypoxia may be caused by loss of large amounts of blood throughhemorrhage, destruction of red blood cells by over-exposure toradiation, reduction in oxygen intake due to high altitudes or prolongedunconsciousness, or various forms of anemia. In response to tissuesundergoing hypoxic stress, EPO will increase red blood cell productionby stimulation of proliferation of erythroid progenitor cells. When thenumber of red blood cells in circulation is greater than needed fornormal tissue oxygen requirements, EPO in circulation is decreased.

Because EPO is essential in the process of red blood cell formation, thehormone has potentially useful applications in both the diagnosis andthe treatment of blood disorders characterized by low or defective redblood cell production. Recent studies have provided a basis for theprojection of efficacy of EPO therapy in a variety of disease states,disorders, and states of hematologic irregularity, including:beta-thalassemia (see, Vedovato et al. (1984) Acta. Haematol.71:211-213); cystic fibrosis (see, Vichinsky et al. (1984) J. Pediatric105:15-21; pregnancy and menstrual disorders (see, Cotes et al. (193)Brit. J. Ostet. Gyneacol. 90:304-311; early anemia of prematurity (see,Haga et al. (1983) Acta Pediatr. Scand. 72; 827-831); spinal cord injury(see, Claus-Walker et al. (1984) Arch. Phys. Med. Rehabil. 65:370-374);space flight (see, Dunn et al. (1984) Eur. J. Appl. Physiol.52:178-182); acute blood loss (see, Miller et al. (1982) Brit. J.Haematol. 52:545-590); aging (see, Udupa et al. (1984) J. Lab. Clin.Med. 103:574-580 and 581-588 and Lipschitz et al. (1983) Blood63:502-509; various neoplastic disease states accompanied by abnormalerythropoiesis (see, Dainiak et al. (1983) Cancer 5:1101-1106 andSchwartz et al. (1983) Otolaryngol. 109:269-272); and renalinsufficiency (see, Eschbach et al. (1987) N. Eng. J. Med. 316:73-78).

Purified, homogeneous EPO has been characterized. See, Hewick U.S. Pat.No. 4,677,195. A DNA sequence encoding EPO was purified, cloned andexpressed to produce synthetic polypeptides with the same biochemicaland immunological properties. A recombinant EPO molecule witholigosaccharides identical to those on the natural material has alsobeen produced. See, Sasaki et al. (1987) J. Biol. Chem. 262:12059-12076.

Despite the availability of purified recombinant EPO, little is knownconcerning the mechanism of EPO-induced erythroblast proliferation anddifferentiation. The specific interaction of EPO with progenitors ofimmature red blood cells, platelets, and megakaryocytes remains to becharacterized. This is due, at least in part, to the small number ofsurface EPO receptor molecules on normal erythroblasts and on theerythroleukemia cell line. See, Krantz and Goldwasser (1984) Proc. Natl.Acad. Sci. USA 81:7574-7578; Branch et al. (1987) Blood 69:1782-1785;Mayeux et al. (1987) FEBS Letters 211:229-233; Mufson and Gesner (1987)Blood 69:148-1490; Sakaguchi et al. (1987) Biochem. Biophys. Res.Commun. 146:7-12; Sawyer et al. (1987) Proc. Natl. Acad. Sci. USA84:3690-3694; Sawyer et al. (1987) J. Biol. Chem. 262:5554-5562; andTodokoro et al. (1988) Proc. Natl. Acad. Sci. USA 84:4126-4130.

Cross-linked complexes between radioiodinated EPO and cell surfaceproteins suggest that the cell surface proteins comprise twopolypeptides having approximate molecular weights of 85,000 daltons and100,000 daltons, respectively. More recently, the two cross-linkedcomplexes have been subjected to V8 protease digestion and have beenfound to have identical peptide fragments, suggesting that the twoEPObinding polypeptides may be products of the same or very similargenes. See, Sawyer et al. (1988) supra. Most cell surface bindingstudies, however, have revealed a single class of binding sites,averaging 300 to 600 per cell surface, with a Kd of approximately 800 pM(picomolar). See, Sawyer et al. (1987) Proc. Natl. Acad. Sci. USA84:3690-3694. However, EPO-responsive splenic erythroblasts, preparedfrom mice injected with the anemic strain (FVA) of the Friend leukemiavirus, demonstrate a high and a low affinity binding site withdissociation constants of 100 pM and 800 pM, respectively. See, Sawyeret al. (1987) J. Biol. Chem. 262:5554-5562 and Landschulz (1989) Blood73:1476-1478. The DNA sequences and encoded peptide sequences for murineand human EPO receptor proteins have been described. See, D'Andrea etal. PCT Patent Publication No. WO 90/08822 (published 1990).

The availability of cloned genes for the EPO-R facilitates the searchfor agonists and antagonists of this important receptor. Theavailability of the recombinant receptor protein allows the study ofreceptor-ligand interaction in a variety of random and semi-randompeptide diversity generation systems. These systems include the"peptides on plasmids" system described in U.S. Pat. No. 5,270,170,filed Oct. 16, 1991, the "peptides on phage" system described in U.S.Pat. No. 5,432,018, filed Jun. 20, 1991, and in Cwirla et al., Aug.1990, Proc. Natl. Acad. Sci. USA 87:6378-6382, the "encoded syntheticlibrary" (ESL) system described in U.S. Pat. No. 5,770,358, filed Sep.16, 1992, which is a continuation-in-part application of Ser. No.762,522, filed Sep. 18, 1991, now abandoned, and the "very large scaleimmobilized polymer synthesis" system described in U.S. Pat. No.5,143,854, filed Mar. 7,1990; PCT patent publication No. 90/15070,published Dec. 13, 1990; U.S. patent application Ser. No. 624,120, filedDec. 6, 1990, now abandoned; Fodor et al., Feb. 15, 1991, Science251:767-773; Dower and Fodor, 1991, Ann. Rep. Med. Chem. 26 :271-180;and U.S. Pat. No. 5,424,156, filed Dec. 6, 1991; each of the foregoingpatent applications and publications is incorporated herein byreference.

There remains a need, however, for compounds that bind to or otherwiseinteract with the EPO-R, both for studies of the important biologicalactivities mediated by this receptor and for treatment of disease. Thepresent invention provides such compounds.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides peptides that bind to andactivate the EPO-R or otherwise behave as EPO agonists. These peptidesare 10 to 40 or more amino acid residues in length, preferably 14 to 20amino acid residues in length, and comprise a core sequence of aminoacids X3X4X5GPX6TWX7X8 (SEQ ID NO:1), where each amino acid is indicatedby standard one letter abbreviation; X3 can be C, A,α-amino-γ-bromobutyric acid, or Hoc, where Hoc is homocysteine; X4 canbe R, H, L, or W; X₅ can be M, F, or I; X₆ is independently selectedfrom any one of the 20 genetically coded L-amino acids or thestereoisomeric D-amino acids; X7 can be D, E, I, L, or V; and X₈ can beC, A, α-amino-γ-bromobutyric acid, or Hoc, where Hoc is homocysteine,provided that either X₃ or X₈ is C or Hoc. Preferably, the peptide willcomprise a core sequence YX2X3X4X5GPX6TWX7X8 (SEQ ID NO:2), where eachamino acid is indicated by standard one letter abbreviation; each X2 andX6 is independently selected from any one of the 20 genetically codedL-amino acids; X3 can be C, A, α-amino-γ-bromobutyric acid, or Hoc,where Hoc is homocysteine; X4 can be R, H, L, or W; X5 can be M, F, orI; X7 can be D, E, I, L, or V; and X8 can be C, A,α-amino-γ-bromobutyric acid, or Hoc, where Hoc is homocysteine, providedthat either X3 or X8 is C or Hoc.

More preferably, the peptide will comprise a core sequence of aminoacids X1YX2X3X4X5GPX6TWX7X8X9X10X11 (SEQ ID NO:3), where each amino acidis indicated by standard one letter abbreviation; each X1, X2, X6, X9,X10, and X11 is independently selected from any one of the 20genetically coded L-amino acids; X3 can be C, A, α-amino-γ-bromobutyricacid, or Hoc, where Hoc is homocysteine; X₄ can be R, H, L, or W; X canbe M, F, or I; X7 can be D, E, I, L, or V; and X8 can be C, A,α-amino-γ-bromobutyric acid, or Hoc, where Hoc is homocysteine, providedthat either X3 or X8 is C or Hoc.

In a more preferred embodiment, both X3 and X8 will be C and, thus, thepeptide will comprise a core sequence of amino acidsX1YX2CX4X5GPX6TWX7CX9X10X11 (SEQ ID NO:4). More preferably, the peptidewill comprise a core sequence of amino acids X1YX2CX4X5GPX6TWX7CX9X10X11(SEQ ID NO:5), where X4 can be R or H; X5 can be F or M; X6 can be I, L,T, M, or V; X7 is D or V; X9 can be G, K, L, Q, R, S, or T; and X10 canbe A, G, P, R, or Y. In a most preferred embodiment, the peptide willcomprise a core sequence of amino acids X1YX2CX4X5GPX6TWX7CX9X10X11 (SEQID NO:6), where X1 can be D, E, L, N, S, T, or V; X2 can be A, H, K, L,M, S, or T; X4 is R or H; Y9 can be K, R, S, or T; and X10 is P.Particularly preferred peptides include but are not limited to, thefollowing:

GGLYLCRFGPVTWDCGYKGG (SEQ ID NO:7);

GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8);

GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9);

VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10);

GGVYACRMGPITWVCSPLGG (SEQ ID NO:11);

VGNYMAHMGPITWVCRPGG (SEQ ID NO:12);

GGTYSCHFGPLTWVCKPQ (SEQ ID NO:13);

GGLYACHMGPMTWVCQPLRG (SEQ ID NO:14);

TIAQYICYMGPETWECRPSPKA (SEQ ID NO:15);

YSCHFGPLTWVCK (SEQ ID NO:16); and

YCHFGPLTWVC (SEQ ID:17).

According to some embodiments of this invention, two or more, andpreferably between two to six amino acid residues, independentlyselected from any of the 20 genetically coded L-amino acids or thestereoisomeric D-amino acids, will be coupled to either or both ends ofthe core sequences described above. For example, the sequence GG willoften be appended to either or both termini of the core sequences forease in synthesis of the peptides. The present invention also providesconjugates of these peptides and derivatives and peptidomimetics of thepeptides that retain the property of EPO-R binding.

The present invention also provides methods for treating diseaseinvolving a deficiency of EPO utilizing the novel compounds of theinvention. The present invention further provides pharmaceuticalcompositions comprising one or more compounds of the invention and aphysiologically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides the sequences of the mutagenesis oligomers employed inthe procedures described herein. N=any nucleotide; K=G or T.

FIG. 2A and B provides the sequences of representative peptides of thisinvention.

FIG. 3 illustrates a new phagemid mutagenesis library constructed usingthe pVIII display system. In this library, the tyrosine, glycine-prolineand threonine-tryptophan residues (underlined) were fixed, as well atthe two cysteines. Other positions between the cysteine residues (shownin outline italic typeface present in the original AF11154 hit peptide)were mutated by oligo construction such that each amino acid residuecould change to any other at a frequency of 50%. "X" denotes a randomamino acid position.

FIGS. 4A-C illustrate pIII and pVIII phagemid mutagenesis librariescurrently under construction and screening. Amino acid residues in boldface are fixed, the remainder (indicated by NNK) are randomized. 4A(ON3007) and 4C (ON3017) are designed to investigate the contribution ofextra flanking regions N-terminal and C-terminal, respectively, to thecore sequence (tyrosine to the second cysteine). 4B (ON3016) is based onpeptide Y-CHFGPLTWVC (SEQ ID NO:17) where the tyrosine residue is placeddirectly next to the first cysteine. This library adds additional randomresidues on both sides of the core sequence.

FIG. 5 illustrates a mutagenesis library, based on GGTYSCHFGPLTWVCKPQGG(SEQ ID NO:8), constructed and screened using a new Lac-I display vector("Headpiece Dimer"). Amino acid residues denoted X are random (NNK),those underlined are lightly mutated (91:3:3:3/91:3:3:3/K), whereasthose in outline are mutated more heavily (70:10:10/70:10:10/K).

FIG. 6 illustrates a mutagenesis library, based onTIAQYICYMGPETWECRPSPKA (SEQ ID NO:15), constructed and screened using anew Lac-I display vector ("Headpiece Dimer"). Amino acid residuesdenoted X are random (NNK), those in outline were fixed, and the twoglutamic acid residues were lightly mutated (91:3:3:3/91:3:3:3/K).

FIG. 7 is a graphical depiction of the results of the FDCP-1/hEPO-Rbioassay for selected peptides of the invention with:

 designating the results for GGCRIGPITWVCGG (SEQ ID NO:19);

o designating the results for GGLYLCRFGPVTWDCGYKGG (SEQ ID NO:7);

▪ designating the results for GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8);

▴ designating the results for GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9);

▾ designating the results for VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10);

| designating the results for GGVYACRMGPYIWVCSPLGG (SEQ ID NO:11);

+ designating the results for VGNYMAHMGPITWVCRPGG (SEQ ID NO:12); and

* designating the results for EPO.

FIG. 8 is a graphical depiction of the results of the TF-1 bioassay forEPO (▴ and ♦ designate the results for the assay using EPO and 10,000 or20,000 cells per well, respectively); and for the peptideVGNYMCHFGPITWVCRPGGG (SEQ ID NO:10) (▪ and  designate the results forthe assay using the peptide and 10,000 or 20,000 cells per well,respectively).

FIGS. 9A (control), 9B (treated with 500 pM EPO) and 9C (treated with 25mm GGDYHCRMGPLTWVCKPLGG) (SEQ ID NO:9) are photographs depicting theresults of a MTT proliferation assay on representative populations ofspleen cells of phenylhydrazine treated mice at 200×magnification.

FIG. 10 is a graphical depiction of the results of the FDCP-1/hEPORbioassay showing increased potency of the biotinylated peptide (i.e.,GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO: 20) (Ahx-biotin)), byoligomerization with streptavidin. Peptides GGTYSCHFGPLTWVCKPQGG (SEQ IDNO:8) and GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO: 20) (Ahx-biotin) exhibitapproximately the same activity, but when the latter is pre-complexedwith streptavidin (i.e., GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20)(Ahx-biotin)-streptavidin complex), it is far more potent. In thisassay, little reduction in activity is seen at the lowest concentration(5 nM with respect to peptide in the complex). Streptavidin, alone, hasmarginal activity at high concentrations.

FIG. 11 is a graphical depiction of the results of the FDCP-1/hEPORbioassay showing polyclonal goat anti-biotin-mediated increase inpotency of peptide AF11505. Pre-complexing GGTYSCHFGPLTWVCKPQGGSSK (SEQID NO:20) (Ahx-biotin) with goat anti-biotin antibodies(GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20)+G anti-B) increases the potencyof the peptide one log over the free peptide. The purified antibodies (Ganti-B) have no stimulatory effect alone.

FIG. 12A and B illustrates the synthetic scheme for the preparation ofthe dimeric peptide analog of GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8).

FIG. 13 illustrates the IC50 plot of the dimeric peptide analog ofGGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8). Affinity was determined using aradioligand competition binding assay against PIG-tailed EPORimmobilized on mAB179.

FIG. 14 illustrates the in vitro biological activity of the dimericpeptide analog of GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) using theFDCP-1/hEPOR cell proliferation assay. The dimeric peptide has an EC50of approximately 20 nM, a 20-fold increase in potency over the parentalpeptide.

FIG. 15 illustrates the cell cycle progression of FDC-P1/ER.

FIGS. 16A and B illustrates the equilibrium binding analysis of thespecific association of [¹²⁵ I]EPO with EBP immobilized on agarose beadsand indicates a Kd of 5 nM±2 based on a linear transformation(Scatchard) of the binding isotherm.

FIGS. 17A, 17B and 17C illustrate the results of the polycythemicexhypoxic mouse bioassay using peptides GGTYSCHFGPLTWVCKPQGG (SEQ IDNO:8), GGTYSCHFGPLTWVCKPQ and LGRKYSCHFGPLTWVCQPAKKD (SEQ ID NO:21),respectively.

FIGS. 18A and 18B illustrate the results of the polycythemic exhypoxicmouse bioassay using peptides TIAQYICYMGPETWECRPSPKA (SEQ ID NO:15) anda dimeric peptide analog of GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)containing two disulfide bonds (AF12080), respectively.

FIGS. 19A and 19B illustrate the results of the reticulocyte assay usingEPO and GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8), respectively. For both dosegroups, n=10 animals. EPO: 0.4,4.0,40.0 Units/mouse, total dose vehiclecontrol; GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8): 2.0,20.0,200.0 μg/mouse,total dose vehicle control+DMSO (1-2%) 200 g/mouse=10 mg/kg. Rational:in vitro proliferation assay data suggests: 2 μg of GGTYSCHFGPLTWVCKPQGG(SEQ ID NO:8)=0.4 Units of EPO.

FIGS. 20A and 20B illustrate the results of the reticulocyte assay usingEPO and GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8), respectively. For both dosegroups, n=10 animals. EPO: 0.4,4.0,40.0 units/mouse, total dose;GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8): increase dose to 1 mg/mouse, totaldose=50 mg/kg and to 2 mg/mouse, total dose=mg/kg.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENT

The following terms are intended to have the following general meanings:

Amino acid residues in peptides are abbreviated as follows:Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is Ile or I;Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Prolineis Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyror Y; Histidine is His or H; Glutarnine is Gln or Q; Asparagine is Asnor N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid isGlu or E; Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Argor R; and Glycine is Gly or G.

Stereoisomers (e.g., D-amino acids) of the twenty conventional aminoacids, unnatural amino acids such as a,a-disubstituted amino acids,N-alkyl amino acids, lactic acid, and other unconventional amino acidsmay also be suitable components for compounds of the present invention.Examples of unconventional amino acids include: 4-hydroxyproline,O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine,5-hydroxylysine, and other similar amino acids and imino acids (e.g.,4-hydroxyproline).

"Agonist" refers to a biologically active ligand which binds to itscomplementary biologically active receptor and activates the lattereither to cause a biological response in the receptor, or to enhancepreexisting biological activity of the receptor.

"Host Cell" refers to a eukaryotic or procaryotic cell or group of cellsthat can be or has been transformed by a recombinant DNA vector. Forpurposes of the present invention, procaryotic host cells are preferred.

"Peptide" or "polypeptide" refers to a polymer in which the monomers arealpha amino acids joined together through amide bonds. Peptides are twoor often more amino acid monomers long.

"Pharmaceutically acceptable salts" refers to the non-toxic alkalimetal, alkaline earth metal, and ammonium salts commonly used in thepharmaceutical industry including the sodium, potassium, lithium,calcium, magnesium, barium, ammonium and protamine zinc salts, which areprepared by methods well known in the art. The term also includesnon-toxic acid addition salts, which are generally prepared by reactingthe compounds of this invention with a suitable organic or inorganicacid. Representative salts include the hydrochloride, hydrobromide,sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napsylate and the like.

"Pharmaceutically or therapeutically effective dose or amount" refers toa dosage level sufficient to induce a desired biological result. Thatresult can be alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system.Preferably, this dose or amount will be sufficient to stimulate theEPO-R and, thus, alleviate the symptoms associated with a deficiency ofEPO, or a defective or low red blood population in vivo.

"Recombinant DNA Cloning or Expression Vector" refers to a DNA or RNAmolecule that encodes a useful function and can be used to transform ahost cell. For purposes of the present invention, a cloning vectortypically serves primarily as an intermediate in the construction of anexpression vector; the latter vector is used to transform or transfect ahost cell so that the transformed host cell produces a protein or otherproduct encoded by the vector. Such vectors are typically "plasmids,"which for purposes of the present invention, are vectors that can beextrachromosomally maintained in a host cell, but can also be vectorsthat integrate into the genome of a host cell. Those of skill in the artmay refer to "cloning vectors", as defined herein, as "vectors" and to"expression vectors," as defined herein, as "plasmids."

The present invention provides compounds that bind to and activate theEPO-R or otherwise behave as an EPO agonist. These compounds include"lead" peptide compounds, discovered with random peptide diversitygenerating systems, and "derivative" compounds constructed so as to havethe same or similar molecular structure or shape as the lead compounds,but that differ from the lead compounds either with respect tosusceptibility to hydrolysis or proteolysis and/or with respect to otherbiological properties, such as increased affinity for the receptor,increased in vitro activity or in vivo activity.

The random peptide diversity generating systems initially employedincluded the "peptides on phage" system discussed above. The randompeptides were designed to be 8 amino acid residues in length, flanked byCys residues at both termini (thus, 10 amino acid residues in totallength). In these initial systems, the random peptides were presented aspart of a fusion protein comprising the pVIII coat protein of a phage fdderivative (peptides on phage). The fusion proteins, along with the DNAencoding the fusion proteins, were "panned" on immobilized EPOR. Thepanning process involved multiple rounds of incubating the fusionproteins with the immobilized receptor, collecting the fusion proteinsthat bound to the receptor (along with the accompanying DNA), andproducing more of the fusion proteins collected.

Typically, after three rounds of panning, the fusion proteins andaccompanying DNA were isolated and cultured to produce fusion proteinpreparations for an ELISA to determine if the fusion protein boundspecifically to the receptor. This assay was carried out similarly tothe panning, except that after removing unbound fusion proteins, thewells were treated with rabbit anti-phage antibody (or with anti-lacantibody for the peptides on plasmids system), then with alkalinephosphatase-conjugated goat anti-rabbit antibody, and then the amount ofalkaline phosphatase in each well was determined by standard methods. Bycomparing test wells with control wells (no receptor), one can determinewhether the fusion proteins bound to the receptor specifically.

The immobilized receptor used in the panning and ELISA procedurescomprised the extracellular domain of the EPO-receptor and was producedin recombinant host cells. This receptor molecule can be produced in avariety of different forms and host cells. One useful form isconstructed with a signal peptide for protein secretion and forglycophospholipid membrane anchor attachment (this form of anchorattachment is called "PIG-tailing;" see, Caras and Weddell, Mar. 3,1989, Science 243:1196-1198; and Lin et al., Aug. 10, 1990, Science249:677-679, each of which is incorporated herein by reference). Thissystem allows for cleavage of the receptor from the surface of the cellsexpressing the receptor and collection of the cleaved receptor quiteeasily. Preferably, a protease cleavage site, such as a thrombincleavage site, is inserted between the HPAP epitope of the PIG-tailedreceptor and the receptor itself.

The recombinant receptor protein was immobilized using the followingmethodology. Microtiter plates were coated within an anti-receptorantibody and the wells which were to contain the immobilized receptorwere treated with bovine serum albumin (BSA) to block non-specificbinding. The PIG-tailed receptor having a thrombin cleavage site wasadded to the coated wells of the microtiter plate, which were thenwashed to remove unbound receptor.

When using random peptide generation systems that allow for multivalentligand-receptor interaction, one must recognize that the density of theimmobilized receptor is an important factor in determining the affinityof the ligands that will bind to the immobilized receptor. At higherreceptor densities (i.e., each anti-receptor antibody-coated welltreated with 0.25 to 0.5 mg of receptor), multivalent binding is morelikely to occur (if at all) than at lower receptor densities (i.e., eachanti-receptor antibody-coated well treated with 0.5 to 1 ng of thereceptor). If multivalent binding is occurring, then one will be morelikely to isolate ligands with relatively low affinity. Typically, onecan identify lead compounds using a high density of immobilized receptorand then test the derivatives of the lead compound at lower receptordensities to isolate compounds with higher affinity for the receptorthan the lead compound.

Often, the receptor was added only to alternate rows of the microtiterplate; the BSA-blocked wells in the "blank" rows served as usefulnegative controls to determine whether a receptor-specific reaction wascreating the observed results. Fusion protein preparations were thenadded to the wells and incubated to allow binding to the receptor tooccur; then, the wells were washed to remove unbound fusion proteins.

With the above systems, a peptide was discovered that bound to theEPO-R. The DNA encoding the fusion protein that bound to the receptorwas sequenced. This peptide had the sequence: GGCRIGPITWVCGG (SEQ IDNO:19) (the N-terminal GG residue allowing for cleavage on the phage).This peptide consistently showed low affinities to BSA and to theanti-receptor antibody and high affinity to EPO-R by ELISA. Moreover,the phagemid clone was competed by free EPO and by cognate free peptide.Further, the free peptide was found to compete EPO-phagemid, LacI-EPOfusion, and radioligand. Finally, the free peptide did not compete inIL-2Rαβ binding assays.

A mutagenesis study on this preferred peptide was then conducted. Togenerate the collection of oligonucleotides that encode the randompeptides, the mutagenesis oligomers shown in FIG. 1 were prepared whereN was nucleotide A, C, G, or T (equimolar; depending on the methodologyemployed, other nucleotides can be employed) and K was G or T(equimolar) in the codon motif (NNK). Those of skill in the art willrecognize that the NNK motif encodes all of the amino acids, encodesonly one stop codon, and reduces codon bias. There are 32 possiblecodons resulting from the NNK motif: 1 for each of 12 amino acids, 2 foreach of 5 amino acids, 3 for each of 3 amino acids, and only one of thethree stop codons.

The mutagenesis fusion proteins, along with the DNA encoding them, againwere "panned" on immobilized EPO-R. The fusion proteins and accompanyingDNA were then isolated and cultured to produce fusion proteinpreparations for an ELISA to determine if the fusion protein boundspecifically to the receptor. Preferred peptides resulting from thisstudy are shown in FIG. 2. These peptides are characterized by the motif"X3X4X5GPX6TWX7X8" (SEQ ID NO:1), where each amino acid is indicated bystandard one letter abbreviation; X6 is independently selected from anyone of the 20 genetically coded L-amino acids or the stereoisomericD-amino acids; X3 can be C, A, α-amino-Y-bromobutyric acid, or Hoc,where Hoc is homocysteine; X4 can be R, H, L, or W; X can be M, F, or I;X7 can be D, E, I, L, or V; and X8 can be C, A, α-amino-γ-bromobutyricacid, or Hoc, where Hoc is homocysteine, provided that either X3 or X8is C or Hoc.

To ascertain a rough indication of the affinity of the peptides, thephage libraries were also screened using an affinity selection protocolwherein the peptides are competed with EPO (100 nM). This process isrepeated typically for two rounds of panning. In subsequent rounds ofpanning, the competition temperature (4° C. to ambient temperature) andtime (15 to 30 minutes) as well as the temperature (4° C. to ambienttemperature) of the wash solutions can be altered to further select forpeptides with high affinity. Using this affinity selection procedure,peptides sharing the common motif "X1YX2CX4X5GPX6TWX7CX9X10X11" (SEQ IDNO:4), where each amino acid is indicated by standard one letterabbreviation; each X1, X2, X6, X9, X10, and X11 is independentlyselected from any one of the 20 genetically coded L-amino acids or thestereoisomeric D-amino acids; X4 can be R, H, L, or W, X5 can be M, F,or I, and X7 can be D, E, I, L, or V, and were isolated. In a morepreferred embodiment, the peptide will comprise a sequence of aminoacids X1YX2CX4X5GPX6TWX7CX8X10X11 (SEQ ID NO:5), where X4 can be R or H,X5 can be F or M, X6 can be I, L, T, M, or V, X7 is D or V, X9 can be G,K, L, Q, R, S, or T, and X10 can be A, G, P, R, or Y. In a mostpreferred embodiment, the core peptide will comprise a sequence of aminoacids X1YX2CX4X5GPX6TWX7CX9X10X11 (SEQ ID NO:6), where X1 can be D, E,L, N, S, T, or V; X2 can be A, H, K, L, M, S, or T; X4 is R or H; X9 canbe K, R, S, or T; and X10 is P.

Examples of representative peptides falling within this motif andisolated during the affinity selection process are shown in the tablesbelow.

                  TABLE 1                                                         ______________________________________                                        Peptides from Affinity Selection Protocol                                     ______________________________________                                        Competition with 100 nM EPO, 15 min, 4° C.                             GGWVTCRMGPITWVCGVHGG (SEQ ID NO:22)                                           GGQLLCGIGPITWVCRWVGG (SEQ ID NO:23)                                           GGLYLCRMGPVTWECQPRGG (SEQ ID NO:24)                                           GGKYSCFMGPTTWVCSPVGRGV                                                                             (SEQ ID NO:25)                                           GGWVYCRIGPITWVCDTNGG (SEQ ID NO:26)                                           GGIYKCLMGPLTWVCTPDGG (SEQ ID NO:27)                                           GGMYYCRMGPMTWVCKGAGG (SEQ ID NO:28)                                           No Competition                                                                GGTTQCWIGPITWVCRARGG (SEQ ID NO:29)                                           GGPYHCRMGPITWVCGPVGG (SEQ ID NO:30)                                           GGEYLCRMGPITWVCERYGG (SEQ ID NO:31)                                           GGEYRCRMGPISWVCSPQGG (SEQ ID NO:32)                                           GGNYTCRFGPLTWECTPQGGGA                                                                             (SEQ ID NO:33)                                           GGNYVCRMGPITWICTPAGG (SEQ ID NO:34)                                           ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Peptides from Affinity Selection Protocol                                     ______________________________________                                        Second Competition with 100 nM EPO, 15 min, ° C.                       GGSWDCRIGPITWVCKWSGG (SEQ ID NO:35)                                           GGDYTCRMGPMTWICTATRG (SEQ ID NO:36)                                           GGDYNCRFGPLTWVCKPSGG (SEQ ID NO:37)                                           GGSYLCRMGPTTWLCTAQRG (SEQ ID NO:38)                                           GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9)                                            VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10)                                           GGLYLCRMGPQTWMCQPGGG (SEQ ID NO:39)                                           GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)                                            GGDYVCRMGPMTWVCAPYGR (SEQ ID NO:40)                                           GGLYECRMGPMTWVCRPGGG (SEQ ID NO:41)                                           GGWYSCLMGPMTWVCKAHRG (SEQ ID NO:42)                                           GGKYYCWMGPMTWVCSPAGG (SEQ ID NO:43)                                           No Competition                                                                GGYVMCRIGPITWVCDIPGG (SEQ ID NO:44)                                           GSCLQCCIGPITWVCRHAGG (SEQ ID NO:45)                                           GGNYFCRMGPITWVCQRSVG (SEQ ID NO:46)                                           GGEYICRMGPLTWECKRTGG (SEQ ID NO:47)                                           GGLYACRMGPITWVCKYMAG (SEQ ID NO:48)                                           GGQYLCTFGPITWLCRGAGGGS                                                                             (SEQ ID NO:49)                                           GGVYACRMGPITWVCSPLGG (SEQ ID NO:11)                                           GGYTTCRMGPITWVCSAHGG (SEQ ID NO:50)                                           ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Peptides from Affinity Selection Protocol                                     ______________________________________                                        Competition with 100 nM EPO, 15 min, Room Temp.                               VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10)                                           GGTYKCWMGPMTWVCRPVGG (SEQ ID NO:51)                                           GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)                                            GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9)                                            GGNYYCRFGPITFECHPTGG (SEQ ID NO:53)                                           GGLYACHMGPMTWVCQPLRGGGS                                                                            (SEQ ID NO:54)                                           GGEYKCYMGPITWVCKPEGG (SEQ ID NO:55)                                           GGDYVCRMGPMTWVCAPYGRGGS                                                                            (SEQ ID NO:56)                                           No Competition                                                                GGNYVCRMGPITWICTPAGG (SEQ ID NO:34)                                           GGDYTCRMGPMTWICTATRG (SEQ ID NO:36)                                           GGEYLCRMGPMTWVCTPVGG (SEQ ID NO:57)                                           GGSYKCRMGPTTWLCTAQRGGGN                                                                            (SEQ ID NO:58)                                           GGLYTCRMGPITWVCLPAGG (SEQ ID NO:59)                                           GGLYKCRMGPMTWVCSPFGG (SEQ ID NO:60)                                           ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Peptides from Affinity Selection Protocol                                     ______________________________________                                        Competition with 100 nM EPO, 30 min, Room Temp.                               GGTYSVHFGPLTWVCKPQGG (SEQ ID NO:8)                                            GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9)                                            VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10)                                           No Competition                                                                GGDYVCRMGPMTWVCAPYGR (SEQ ID NO:40)                                           GGDYNCRFGPLTWVCKPSGG (SEQ ID NO:37)                                           ______________________________________                                    

Another mutagenesis library having six random amino acid residuesadjacent to a random 8-mer flanked by two cysteine residues was alsoscreened against immobilized EPO-R. The mutagenesis fusion proteins,along with the DNA encoding them, again were "panned" on immobilizedEPO-R. The fusion proteins and accompanying DNA were then isolated andcultured to produce fusion protein preparations for an ELISA todetermine if the fusion protein bound specifically to the receptor. Thepreferred peptide resulting from this study had the sequenceGGPHHVYACRMGPLTWIC (SEQ ID NO:61) and, thus, is encompassed by the coresequence "YX2X3X4X5GPX6TWX7X8" (SEQ ID NO:2), where each amino acid isindicated by standard one letter abbreviation; each X2 and X6 isindependently selected from any one of the 20 genetically coded L-aminoacids or the stereoisomeric D-amino acids; X3 can be C, A,α-amino-γ-bromobutyric acid, or Hoc, where Hoc is homocysteine; X4 canbe R, H, L, or W; X5 can be M, F, or I; X7 can be D, E, I, L, or V; andX8 can be C, A, α-amino-γ-bromobutyric acid, or Hoc, where Hoc ishomocysteine, provided that either X3 or X is C or Hoc, wherein the coresequence is coupled at its amino terminus to a six amino acid unit,wherein each amino acid is independently selected from any of the 20genetically coded L-amino acids or the stereoisomeric D-amino acids.

IC50s were calculated for several of the peptides falling within thegeneral motifs described above. These values were determined using thefree peptide and are shown in Table 5 below. (Each of these peptideswere independently synthesized and are C-terminally amidated, but couldbe easily prepared as the free carboxy acid or as an ester or othercarboxy amide.)

                  TABLE 5                                                         ______________________________________                                        Peptide                    IC.sub.50                                          ______________________________________                                        GGLYLCRFGPVTWDCGYKGG (SEQ ID NO:7)                                                                       1.67 •M                                      GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)                                                                       237  nm                                            GGDYHCRMGPLTWVCKPLGG (SEQ ID NO:9)                                                                       179  nm                                            VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10)                                                                      420  nm                                            GGVYACRMGPITWVCSPLGG (SEQ ID NO:11)                                                                      352  nm                                            VGNYMAHMGPITWVCRPGG (SEQ ID NO:12)                                                                       67   •M                                      ______________________________________                                    

In addition to the foregoing, other mutagenesis studies were carried onthis high affinity EPO agonist family of peptides under conditionsdesigned to enrich for higher affinity peptides. As previouslydescribed, to enrich for higher affinity peptides, libraries arescreened using an affinity selection protocol wherein the peptides arecompeted with EPO (100 nM). This process is typically repeated for tworounds of panning. In subsequent rounds of panning, the competitiontemperature (4° C. to ambient temperature) and time (15 to 30 minutes)as well as the temperature of the wash solutions (4° C. to ambienttemperature) can be altered to further select for peptides with highaffinity. Using these techniques, a mutagenesis library having threerandom amino acid residues on either side of the flanking sequenceYXCRIGPITWVC (SEQ ID NO:62) was also screened against immobilized EPO-R(see, FIG. 3). The mutagenesis fusion proteins, along with the DNAencoding them, again were "panned" on immobilized EPO-R. The fusionproteins and accompanying DNA were then isolated and cultured to producefusion protein preparations for an ELISA to determine if the fusionprotein bound specifically to the receptor. Preferred peptides resultingfrom this study are set forth in Table 6, infra.

                  TABLE 6                                                         ______________________________________                                        GGEYICVMGPNTWVCSPTRGHGS                                                                            SEQ ID NO:63)                                            GGEYLCRMGPMTWVSPFTRKGG                                                                             (SEQ ID NO:64)                                           GGQYICRFGPITWQSQPAGGGS                                                                              (SEQ ID NO:65)                                          GREYSCRMGPITWVCMPRASLGS                                                                            (SEQ ID NO:66)                                           GDYLCSMGPITWICVPERGGGS                                                                              (SEQ ID NO:67)                                          ELWYSCRMGPVTWMCGRYQGGGS                                                                            (SEQ ID NO:68)                                           ______________________________________                                    

In another mutagenesis study, a mutagenesis library having the stronglyconserved residues (i.e., Y, C, G, P, T and W) fixed, the other residuesrandomized and 10 additional residues at the N-terminus before thetyrosine was also screened against immobilized EPO-R (see, FIG. 4A). Themutagenesis fusion proteins, along with the DNA encoding them, againwere "panned" on immobilized EPO-R. The fusion proteins and accompanyingDNA were then isolated and cultured to produce fusion proteinpreparations for an ELISA to determine if the fusion protein boundspecifically to the receptor. Preferred peptides resulting from thisstudy are set forth in Table 7, infra.

                  TABLE 7                                                         ______________________________________                                        QICRADRKGIYQCWYGPETWICgg                                                                            (SEQ ID NO:69)                                          QQGYSLWLPWYNCVLGPYTWVCgg                                                                            (SEQ ID NO:70)                                          YGGSAAVPWKYGCSLGPVTWVCgg                                                                            (SEQ ID NO:71)                                          QIVSWGLYSGYLCMVGPVTWLCgg                                                                            (SEQ ID NO:72)                                          GSGALSAAGWYGCRVGPLTWVCgg                                                                            (SEQ ID NO:73)                                          SVVSHDAAGVYDCVIGPVTWICgg                                                                            (SEQ ID NO:74)                                          IYSWTGILGSYVCWYGPDTWVCgg                                                                            (SEQ ID NO:75)                                          SCIYVRFFYCYQCSEGPATWLCgg                                                                            (SEQ ID NO:76)                                          TVAKGQSGVRYSCLRGPETWVCgg                                                                            (SEQ ID NO:77)                                          VQPQYKWATMYQCWKGPSTWFCgg                                                                            (SEQ ID NO:78)                                          KSGCWEMGSSYQCARGPRTWCCgg                                                                            (SEQ ID NO:79)                                          CSVRRMDREYYRCCRGPFTWQCgg                                                                            (SEQ ID NO:80)                                          KYQEEMFMGYQCLQGPKTQLCgg                                                                             (SEQ ID NO:81)                                          VCPGSEFRVGYICAMGPYTWDCgg                                                                            (SEQ ID NO:82)                                          SLCSSRCNSPYFCSIGPSTWRCgg                                                                            (SEQ ID NO:83)                                          QASLGLPLKQYLCVLGPHTWLCgg                                                                            (SEQ ID NO:84)                                          ACKPAALFVQYGCVLGPMTWICgg                                                                            (SEQ ID NO:85)                                          SCERAGGRWEYVCQWGPDTWLCgg                                                                            (SEQ ID NO:86)                                          RVARQVQQVSYWCAHGPATCYCgg                                                                            (SEQ ID NO:87)                                          HKYDTLMLTNYVCQRGPLTQLCgg                                                                            (SEQ ID NO:88)                                          ______________________________________                                    

In still another mutagenesis study, a mutagenesis library having thestrongly conserved residues (i.e., Y, C, G, P, T and W) fixed, the otherresidues randomized and 10 additional residues between the secondcysteine and the (Gly)4-Ser (SEQ ID NO:240) linker was also screenedagainst immobilized EPOR (see, FIG. 4B). In this library, the conservedtyrosine residue was preceded by two glycine residue to allow forefficient signal peptide cleavage. The mutagenesis fusion proteins,along with the DNA encoding them, again were "panned" on immobilizedEPO-R. The fusion proteins and accompanying DNA were then isolated andcultured to produce fusion protein preparations for an ELISA todetermine if the fusion protein bound specifically to the receptor.Preferred peptides resulting from this study are set forth in Table 8,infra.

                  TABLE 8                                                         ______________________________________                                        GgYHCEWGPETWICRPEISPLTVMgg                                                                         (SEQ ID NO:89)                                           GgYICDYGPLTWACKPAGATLLQPgg                                                                         (SEQ ID NO:90)                                           GgYTCRFGPVTWDCLPAINHNGVLgg                                                                          (SEQ ID NO:91)                                          ggYQ*FMGPETWVCAPEPRVERVSgg                                                                          (SEQ ID NO:241)                                         ggYLCRFGPETWTCAPERSVVTQSgg                                                                          (SEQ ID NO:242)                                         ggYVCDFGPTTWICRGQVMEHINTgg                                                                          (SEQ ID NO:92)                                          ggYMCNMGPLTWDCSPVRSTSMAWgg                                                                          (SEQ ID NO:93)                                          ggYNCTMGPNTWVCTPAAESPAVFgg                                                                          (SEQ ID NO:94)                                          ggYGCRIGPITWICDDVSRSPRA                                                                             (SEQ ID NO:95)                                          ggYTCRMGPQTWECLPMSEGV                                                                               (SEQ ID NO:96)                                          ggYNCKFGPQTWDCSSANLKEV                                                                              (SEQ ID NO:97)                                          Gylcemgpetwmcrpedaklgv                                                                              (SEQ ID NO:98)                                          GgYGCKFGPVTWICEDLLLDPMY                                                                             (SEQ ID NO:99)                                          GgYNCKFGPQTWDCSSANLKEVLV                                                                            (SEQ ID NO:100)                                         GYLCEMGPETWMCRPEDCEAW                                                                               (SEQ ID NO:101)                                         GgYGCGLAPVTWECPQVSIPYGLSgg                                                                          (SEQ ID NO:102)                                         GgYGCRIGPTTWICDSTVPQLREVgg                                                                          (SEQ ID NO:103)                                         GgYRCSWAPETWVCDNHSA   (SEQ ID NO:104)                                         GYLCNFGPITWDCVSSAQSEMQIgg                                                                           (SEQ ID NO:105)                                         ______________________________________                                    

In yet another mutagenesis study, a mutagenesis library having thestrongly conserved residues (i.e., Y, C, G, P, T and W) fixed with thetyrosine placed directly next to the first cysteine and the other aminoacids randomized, including 4 residues N-terminal to the tyrosine and 5between the second cysteine and the linker, was also screened againstimmobilized EPOR (see, FIG. 4C). The N-terminal random amino acids wereagain preceded by two glycine residues to allow for efficientprocessing. The mutagenesis fusion proteins, along with the DNA encodingthem, again were "panned" on immobilized EPOR. The fusion proteins andaccompanying DNA were then isolated and cultured to produce fusionprotein preparations for an ELISA to determine if the fusion proteinbound specifically to the receptor. Preferred peptides resulting fromthis study are set forth in Table 9, infra.

                  TABLE 9                                                         ______________________________________                                        GgAELQYCKIGPETWVCDWPHIgg                                                                            (SEQ ID NO:106)                                         GgPYEGYCSGGPVTWECCVSVCgg                                                                            (SEQ ID NO:107)                                         GgQPLPYCSPGPTTWFCINWLFgg                                                                            (SEQ ID NO:108)                                         GgCSYGYCPMGPFTWMCRQRRLgg                                                                            (SEQ ID NO:109)                                         GgVRGSYCQSGPPTWQCDLRFFgg                                                                            (SEQ ID NO:110)                                         GgRCARYCACGPGTWNCLGRCQgg                                                                            (SEQ ID NO:111)                                         GgLGRCYCVYGPLTWWCSQTSLgg                                                                            (SEQ ID NO:112)                                         GgLCVWYCSAGPWTWYCIYRSAgg                                                                            (SEQ ID NO:113)                                         GgKPGPYCSFGPETWVCTALGMgg                                                                            (SEQ ID NO:114)                                         ggRLGEYCEIGPITWICRLFLPgg                                                                            (SEQ ID NO:115)                                         ggPGLGYCDFGPLTWVCDGSVDgg                                                                            (SEQ ID NO:116)                                         ggLSSAYCRYGPETWICWAGTGgg                                                                            (SEQ ID NO:117)                                         ggVLHLYCYYGPETWDCLPIKAgg                                                                            (SEQ ID NO:118)                                         ggGGGVYCLVGPVTWLCGPAAMgg                                                                            (SEQ ID NO:119)                                         ggLTRNYCRIGPETWICQEVAIgg                                                                            (SEQ ID NO:120)                                         ggWSERYCVLGPLTWECVHLFAgg                                                                            (SEQ ID NO:121)                                         ggMPLKYCGMGPVTWVCCEAVSgg                                                                            (SEQ ID NO:122)                                         ggSVMRYCHFGPETWICPYDMPgg                                                                            (SEQ ID NO:123)                                         ggALYPYCLIGPMTWVCQVGWIgg                                                                            (SEQ ID NO:124)                                         ggTYGNYCRGGPGTWHCEDTRGgg                                                                            (SEQ ID NO:125)                                         ggASYCYCSKGPATWKCVGSILgg                                                                            (SEQ ID NO:126)                                         ggSLAAYCLQGPKTWPCVRRRLgg                                                                            (SEQ ID NO:127)                                         ggTDSLYCKLGPLTWHCQLYQKgg                                                                            (SEQ ID NO:128)                                         gISQQYCWRGPATWVCLEWELgg                                                                             (SEQ ID NO:129)                                         ______________________________________                                    

In addition to the foregoing mutagenesis studies, mutagenesis of peptideGGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) was performed using a modifiedC-terminal Lac-I display system in which display valency was reducedwith the aim of identifying higher affinity hits ("Headpiece Dimer").The Lac-I Headpiece Dimer (HPD) Display system is described in greaterdetail in U.S. Pat. No. 5,338,665, which is hereby incorporated byreference for all purposes. Essentially, the residues which were highlyconserved in the previous mutagenesis studies (i.e., Y, C, G, P, T andW) were mutated lightly, whereas the less conserved residues (i.e., H,F, L and V) were subject to a higher level of mutation. Four randomresidues proceeded the tyrosine residue, the latter being also followedby one random residue. The C-terminus of the mutagenesis scheme endedwith 6 random amino acids, following the cysteine. The details of thelibrary construction are set forth in FIG. 5.

The library was screened through four rounds on PIG-tailed EPO-Rimmunobilized on mAb179, employing EPO elution from round two onward toenrich for higher affinity clones. The resulting DNA inserts were thencloned as a pool into a maltose binding protein (MBP) vector allowingtheir expression as a C-terminal fusion protein. Crude cell lysates fromrandomly picked individual MBP fusion clones were then assayed for EPO-Rbinding in an ELISA format. Preferred peptides resulting from this studyare set forth in Table 10, infra.

                  TABLE 10                                                        ______________________________________                                        RTKEYSCQMGPLTWICVPKS                                                                              (SEQ ID NO:130)                                           SKARYMCHMGPLTWVCRPEV                                                                              (SEQ ID NO:131)                                           GGKAYMCRLGPVTWVCSPRIKL                                                                            (SEQ ID NO:132)                                           LLRGYECYMGPLTWVCRSSKPR                                                                            (SEQ ID NO:133)                                           TIAQYICYMGPETWECRPSPKA                                                                            (SEQ ID NO:15)                                            NGRTYSCQLGPVTWVCSRGVRR                                                                            (SEQ ID NO:134)                                           LGRKYSCHFGPLTWVCQPAKKD                                                                            (SEQ ID NO:21)                                            MKTKYKCYMGPLTWVCEGS (SEQ ID NO:135)                                           SKTKYRCEMGPLTWVCERW (SEQ ID NO:136)                                           LTRLYSCHMGPSTWVCSTALRK                                                                            (SEQ ID NO:137)                                           RGQLYACHFGPVTWVCKRRKRV                                                                            (SEQ ID NO:138)                                           SGILYECHMGPLTWVCTPSRRR                                                                            (SEQ ID NO:139)                                           GSKTYSCQLGPVTWVCGRKR                                                                              (SEQ ID NO:140)                                           ARGKYQCQFGPLTWECLPIRPR                                                                            (SEQ ID NO:141)                                           VTRMYRCRMGPLTWVCER  (SEQ ID NO:142)                                           KPSLYECHLGPLTWECRPRRRE                                                                            (SEQ ID NO:143)                                           RGHMYSCQLGPVTWVCKPLSGR                                                                            (SEQ ID NO:144)                                           ITPTYHCKFGPQTWVCAPKRSALTK                                                                         (SEQ ID NO:145)                                           GNRMYQCHMGPLTWVCQPTRIH                                                                            (SEQ ID NO:146)                                           MKTKYKCYMGPLTWVCEGSRLK                                                                            (SEQ ID NO:147)                                           HLGKYDCSFGPQTWVCKPRRSL                                                                            (SEQ ID NO:148)                                           ERRVYECQMGPLTWECKPGVKG                                                                            (SEQ ID NO:149)                                           LGRKYSCHFGPVTWVCQPAKKD                                                                            (SEQ ID NO:243)                                           RGRGYSCQMGPVTWVCKRERYF                                                                            (SEQ ID NO:150)                                           RLREYRCHMGPQTWVCNGHHSK                                                                            (SEQ ID NO:151)                                           SGALYDCQMGPITWVCRANRQK                                                                            (SEQ ID NO:152)                                           TNQVYGCKFGPKTWVCKPAPRI                                                                            (SEQ ID NO:153)                                           TRGMYACHMGPQTWVCRPTQPR                                                                            (SEQ ID NO:154)                                           VLSNYECTMGPKTWVCKPLRLK                                                                            (SEQ ID NO:155)                                           ______________________________________                                    

One of the most striking features of the peptides obtained using theLac-I Headpiece Dimer Display system is the accumulation of multiplepositive charges in the regions flanking the conserved cysteines,particularly so in RGQLYACHFGPVTWVCKRRKRV (SEQ ID NO:138), which has aC-terminal stretch of 5 such residues. Amino acids which were lightlymutagenized (i.e., Y, C, G, P, T and W) were absolutely conserved,whereas new motifs were generated at those positions which were moreheavily mutated. Of particular interest is the presence of an additionaltyrosine residue in a number of the peptides (see, e.g.,LLRGYECYMGPLTWVCRSSKPR) (SEQ ID NO:133), and the presence of twoglutamic acid residues between the cysteines in TIAQYICYMGPETWECRPSPKA(SEQ ID NO:15)

In addition to the foregoing mutagenesis studies, mutagenesis of peptideTIAQYICYMGPETWECRPSPKA (SEQ ID NO:15) was performed using a modifiedC-terminal Lac-I display system similar to the system previouslydescribed. Essentially, the residues which were highly conserved inprevious mutagenesis studies (i.e., Y, C, G, P, T and W) were fixed,whereas the less conserved residues (i.e., H, F, L and V) wererandomized. In addition, the two glutamic acid residues were lightlymutated. Four random residues proceeded the tyrosine residue, the latterbeing also followed by one random residue. The C-terminus of themutagenesis scheme ended with 6 random amino acids following thecysteine. The details of the library construction are set forth in FIG.6.

The library was screened through three rounds on PIG-tailed EPO-Rimmunobilized on mAb179, employing EPO elution from round two onward toenrich for higher affinity clones. Colony lifts were performed probingwith the human Fcγ-EBP reagent, followed by goat anti-human Fcγconjugated to akaline phosphatase the latter of which is available fromSigma Chemical Co., St. Louis, Mo. Thereafter, the HPD plasmidsidentified were sequenced. Peptides resulting from this study are setforth in Table 11, infra.

                  TABLE 11                                                        ______________________________________                                        ALKKYDCYFQPETWECLARRPH                                                                             (SEQ ID NO:156)                                          ERRFYKCRFGPETWECTL    (SEQ ID NO:157)                                         FGQEYRCHLGPETWQCSPVRVG                                                                              (SEQ ID NO:158)                                         FRPEYMCRMGPETWECGGARP                                                                               (SEQ ID NO:159)                                         GSRKYWCRMGPETWECMKPVRL                                                                              (SEQ ID NO:160)                                         GLKAYGCRYGPETWDCRSVILI                                                                              (SEQ ID NO:161)                                         IRQPYICHMGPETWECGRYPAG                                                                              (SEQ ID NO:162)                                         KGASYHCIMGPETWECIPQRVW                                                                              (SEQ ID NO:163)                                         MKQLYSCIMGPETWECRPGVER                                                                             (SEQ ID NO:164)                                          QRHYYRCALGPETWECRPMSPE                                                                              (SEQ ID NO:165)                                         TKRLYHCHMGPETWECHGPMRK                                                                              (SEQ ID NO:166)                                         TRPSYRCAFGPVTWECIPAR  (SEQ ID NO:167)                                         RHKSYVCTFGPETWECTGAIRR                                                                              (SEQ ID NO:168)                                         RGRMYNCRMGPETWECKGQSKD                                                                              (SEQ ID NO:169)                                         RRRYYRCWMGPETWECSPVSNK                                                                              (SEQ ID NO:170)                                         VADNYDCPIGPVTWECIHVRAS                                                                              (SEQ ID NO:171)                                         VQKKYLCHFGPETWECGPDRD                                                                               (SEQ ID NO:172)                                         WQTWYICERGPETWECRWLVL                                                                               (SEQ ID NO:173)                                         YRMPYRCKMGPETWECVGGRGR                                                                              (SEQ ID NO:174)                                         YSREYSCRMGPETWECXRGFLR                                                                              (SEQ ID NO:175)                                         ______________________________________                                    

The foregoing pool of peptide sequences were then cloned into a maltosebinding protein (MBP) vector allowing their expression as a C-terminalfusion protein. Crude cell lysates from randomly picked individual MBPfusion clones were then assayed for EPOR binding in an ELISA format.Preferred peptides resulting from this study are set forth in Table 12,infra.

                  TABLE 12                                                        ______________________________________                                        RSMWYRCQMGPQTWVCGPRSAS                                                                             (SEQ ID NO:176)                                          SRREYICHLGPQTWVCGPGGRK                                                                              (SEQ ID NO:177)                                         GSPSYHCHLGPLTWVCKPHRMR                                                                              (SEQ ID NO:178)                                         MVGRYQCHMGPRTWVCKPWHG                                                                               (SEQ ID NO:179)                                         GTARYQCHFGPLTWVCKPSLKG                                                                              (SEQ ID NO:180)                                         ELRGYICHFGPVTWVCKPNGSR                                                                              (SEQ ID NO:181)                                         LKQGYQCQLGPQTWVCRPLRMP                                                                              (SEQ ID NO:182)                                         KERKYECQFGPRTWVCQPTRAN                                                                              (SEQ ID NO:183)                                         VRKVYACHMGPVTWVCVPGYKG                                                                              (SEQ ID NO:184)                                         SGQRYVCRMGPETWVCRSYRGL                                                                              (SEQ ID NO:185)                                         ERRSYSCQMGPVTWVCGRQMGQ                                                                              (SEQ ID NO:186)                                         VKNNYRCQFGPVTWVCKAFR  (SEQ ID NO:187)                                         SGASYDCQMGPITWVCRANRQK                                                                              (SEQ ID NO:188)                                         ______________________________________                                    

Representative peptides which were found to bind specifically to theEPO-receptor were also tested in cell-based functional assays. One assayutilized FDCP-1, a growth factor dependent murine multi-potentialprimitive hematopoietic progenitor cell line (see, e.g., Dexter et al.(1980) J. Exp. Med. 152:1036-1047), as the parental cell line. This cellline can proliferate, but not differentiate, when supplemented withWEHI3-conditioned media (a medium that contains IL-3, ATCC numberT1B68). The parental cell line is transfected with the human or murineEPO-R as described below to produce the FDCP-1-hEPO-R or FDCP-1-mEPO-Rcell line, respectively. These transfected cell lines can proliferate,but not differentiate, in the presence of human or murine EPO.

In brief, the cells are grown to half stationary density in the presenceof the necessary growth factors. The cells are then washed in PBS andstarved for 16-24 hours in whole media without the growth factors. Afterdetermining the viability of the cells, stock solutions (in whole mediawithout the growth factors) are made to give about 10⁵ cells per 50microliters. Serial dilutions of the compounds (typically the free,solution phase peptide as opposed to a phage-bound or other bound orimmobilized peptide) to be tested are made in 96-well tissue cultureplates for a final volume of 50 microliters per well. Cells (50microliters) are added to each well and the cells are incubated 24-48hours, at which point the negative controls should die or be quiescent.Cell proliferation is then measured by techniques known in the art, suchas an MTT assay which correlates with ³ H-thymidine incorporation as anindication of cell proliferation (see, Mosmann (1983) J. Immunol.Methods 65:55). FIG. 7 illustrates the results of this assay for EPO andfor the peptides listed in Table 5 above. Peptides which bind to the EPOreceptor and exhibit activity in the FDCP-1/hEPO-R cell based bioassayare preferred compounds of the invention.

A second cell based assay utilized the TF-1 cell line. See, Kitamura etal. (1989) Blood 73:375-380, which is incorporated herein by reference.Representative results are shown in FIG. 8. FIG. 8 depicts the effectsof EPO and the free peptide VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10) oncellular proliferation of the cell line TF-1.

Another cell based assay which further illustrates the ability of thecompounds of this invention to act as EPO agonists is based on ³H-thymidine incorporation into spleen cells of phenylhydrazine treatedmice. The results of this assay are shown in FIGS. 9A-9C.

Other biological assays that can be used to demonstrate the activity ofthe compounds of the present invention are disclosed in Greenberger etal. (1983) Proc. Natl. Acad. Sci. USA 80:2931-2935 (EPO-dependenthematopoietic progenitor cell line); Quelle and Wojchowski (1991) J.Biol. Chem. 266:609-614 (protein tyrosine phosphorylation in B6SUt.EPcells); Dusanter-Fourt et al. (1992) J. Biol. Chem. 287:10670-10678(tyrosine phosphorylation of EPO-receptor in human EPO-responsivecells); Quelle et al. (1992) J. Biol. Chem. 267:17055-17060 (tyrosinephosphorylation of a cytosolic protein (pp100) in FDC-ER cells);Worthington et al. (1987) Exp. Hematol. 15:85-92 (colorimetric assay forhemoglobin); Kaiho and Miuno (1985) Anal. Biochem. 149:117-120(detection of hemoglobin with 2,7-diaminofluorene); Patel et al. (1992)J. Biol. Chem. 267:21300-21302 (expression of c-myb; Witthuhn et al.(1993) Cell 74:227-236 (association and tyrosine phosphorylation ofJAK2); Leonard et al. (1993) Blood 82:1071-1079 (expression of GATAtranscription factors); Ando et al. (1993) Proc. Natl. Acad. Sci. USA90:9571-9575 (regulation of G1/3 transition by cycling D2 and D3); andcalcium flux, each of which is incorporated herein by reference.

An instrument designed by Molecular Devices Corp., known as amicrophysiometer, has been reported to be successfully used formeasurement of the effect of agonists and antagonists on variousreceptors. The basis for this apparatus is the measurement of thealterations in the acidification rate of the extracellular media inresponse to receptor activation.

According to a preferred embodiment, the peptides of the presentinvention are dimerized or oligomerized, thereby increasing the affinityand/or activity of the lead compounds disclosed herein. To investigatethe effect that peptide dimerization/oligomerization has on EPO mimeticpotency in cell proliferation assays, a C-terminally biotinylated analogof GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) was synthesized (i.e.,GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20) Ahx-biotin).

This peptide was incubated with streptavidin in PBS at a 4:1 molar ratioat room temperature for one hour. Following this, the complex wasintroduced into the PIG-tailed EPO-R binding assay for IC50determination. Peptide that had not been complexed to streptavidin wasalso run in the same experiment. Pre-complexed peptide was found to havean IC50 of 20 nM compared to the 350 nM IC50 of peptide that had notbeen incubated with streptavidin. This greater than 10-fold increase inapparent affinity is presumably due to the multivalent state of thepeptide-streptavidin complex. Since this comparison was made using thefree peptide concentrations and not the effective complex concentration(theoretically 4-fold lower), the effect will be even greater.

In addition, this peptide was preincubated with streptavidin inserum-free HEPES-buffered RPMI at a 4:1 molar ratio, as above. Thecomplex was tested for stimulation of cell proliferation in anFDCP-1/hEPO-R bioassay alongside free GGTYSCHFGPLTWVCKPQGGSSK (SEQ IDNO:20) (Ahx-biotin)) and the unbiotinylated parental peptide, i.e.,GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8). FIG. 10 illustrates the results ofthe assay where the EPO-ED50 of the free peptides were similar(approximately 1 μM), but that of the pre-formed streptavidin complexwas less than 10 nM, a two log reduction in EPO-ED50. Streptavidin,alone, had some small stimulatory effect at the highest concentrations,presumably due to contamination with bacterial endotoxin.

In addition, an increase in biological potency was found when thepeptide was dimerization with goat anti-biotin IgG. FIG. 11 illustratesthat a one log reduction in EPO-ED50 can also be achieved bypreincubation of GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20) (Ahx-biotin)with purified goat anti-biotin IgG at a 2:1 molar ratio. This increasein biological potency is presumably due to the dimerization of thepeptide by the antibodies. The anti-biotin antibodies alone had noeffect on the cells. Moreover, a 100-fold reduction in EPO-ED50 was seenwith the GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20)(Ahx-biotin)-streptavidin complex. As such, by dimerizing oroligomerizing the lead peptides of the present invention, the affinityand/or activity of such peptides can be increased.

In another embodiment, a dimeric peptide analog of GGTYSCHFGPLTWVCKPQGG(SEQ ID NO:8) containing two disulfide bonds was prepared using thegeneral scheme set forth in FIG. 12. Briefly, the first peptide chainwas assembled on a Tentagel resin. The Fmoc-Lys(Alloc) was coupled tothe Knorr linker, the Alloc group being used as an orthogonal protectinggroup. For the first peptide chain, Cys(Acm) was used. After thecompletion of the first peptide chain, the Alloc group was removed andthe second peptide chain was built upon the side chain amines of thelysine residue. In this peptide chain, Cys(trt) was used. After thesynthesis was completed, the peptide was cleaved from the resin andpurified. The peptide was then cyclized to a compound containing asingle disulfide bond. Thereafter, the second disulfide bond was formedby iodine oxidation, yielding the bi-cyclic dimer.

FIGS. 13 and 14 show the in vitro EPOR binding and biological activitiesof the dimer. The affinity of the dimer was tested against thePIG-tailed EPOR immobilized on mAb179 in strip wells. The result of theequilibrium competition binding assay indicated an affinity ofapproximately 2 nM, a 200-fold increase over the value for the parentalpeptide, GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8), (200 nM), and 5-fold overthe GGTYSCHFGPLTWVCKPQGGSSK (SEQ ID NO:20) (Ahx-biotin)-streptavidincomplex. In vitro bioactivity, as measured by FDCP-1/hEPOR cellproliferation, was increased approximately 20-fold from an EC50 of 400nM (for the parental peptide) to 20 nM. As such, by dimerizing oroligomerizing the lead peptides of the present invention, the affinityand/or activity of such peptides can be significantly increased.

The peptides of this invention or derivatives thereof can be conjugatedto compounds that bind to the EPO-R to construct compounds with anaffinity for the receptor greater than either of the compounds of whichthe conjugate is composed. The discovery of these peptides alsofacilitates the identification of peptides that bind to the same site onthe EPO-R, because one can bias the library or panning procedure toeliminate peptides with the complementary "non-blocking" motif.

The preferred motif sequence also provides a means to determine theminimum size of an EPO agonist of the invention. Using the "encodedsynthetic library" (ESL) system described in U.S. patent applicationSer. No. 946,239, filed Sep. 16, 1992, which is a continuation-in-partapplication of Ser. No. 762,522, filed Sep. 18, 1991, or the "very largescale immobilized polymer synthesis" system described in U.S. patentapplication Ser. Nos. 492,462, filed Mar. 7, 1990; Ser. No. 624,120,filed Dec. 6, 1990; and Ser. No. 805,727, filed Dec. 6, 1991; one cannot only determine the minimum size of a peptide with such activity, onecan also make all of the peptides that form the group of peptides thatdiffer from the preferred motif (or the minimum size of that motif) inone, two, or more residues. This collection of peptides can then bescreened for the ability to bind to EPO-receptor. This immobilizedpolymer synthesis system or other peptide synthesis methods can also beused to synthesize every truncation analog and every deletion analog andevery combination of truncation and deletion analog of all of thepeptide compounds of the invention.

The peptides of the invention can also be prepared by classical methodsknown in the art, for example, by using standard solid phase techniques.The standard methods include exclusive solid phase synthesis, partialsolid phase synthesis methods, fragment condensation, classical solutionsynthesis, and even by recombinant DNA technology. See, e.g.,Merrifield, 1963, J. Am. Chem. Soc. 85:2149, incorporated herein byreference. On solid phase, the synthesis is typically commenced from theC-terminal end of the peptide using an α-amino protected resin. Asuitable starting material can be prepared, for instance, by attachingthe required α-amino acid to a chloromethylated resin, a hydroxymethylresin, or a benzhydrylamine resin. One such chloromethylated resin issold under the tradename BIO-BEADS SX-1 by Bio Rad Laboratories,Richmond, Calif., and the preparation of the hydroxymethyl resin isdescribed by Bodonszky et al., 1966, Chem. Ind. (London) 38:1597. Thebenzhydrylamine (BHA) resin has been described by Pietta and Marshall,1970, Chem. Commn. 650, and is commercially available from BeckmanInstruments, Inc., Palo Alto, Calif., in the hydrochloride form.

Thus, the compounds of the invention can be prepared by coupling anα-amino protected amino acid to the chloromethylated resin with the aidof, for example, cesium bicarbonate catalyst, according to the methoddescribed by Gisin, 1973, Helv. Chim. Acta 56:1467. After the initialcoupling, the α-amino protecting group is removed by a choice ofreagents including trifluoroacetic acid (TFA) or hydrochloric acid (HCl)solutions in organic solvents at room temperature.

The α-amino protecting groups are those known to be useful in the art ofstepwise synthesis of peptides. Included are acyl type protecting groups(e.g., formyl, trifluoroacetyl, acetyl), aromatic urethane typeprotecting groups (e.g., benzyloxycarboyl (Cbz) and substituted Cbz),aliphatic urethane protecting groups (e.g., t-butyloxycarbonyl (Boc),isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protectinggroups (e.g., benzyl, triphenylmethyl). Fmoc is a preferred protectinggroup. The side chain protecting group (typically ethers, esters,trityl, PMC, and the like) remains intact during coupling and is notsplit off during the. deprotection of the amino-terminus protectinggroup or during coupling. The side chain protecting group must beremovable upon the completion of the synthesis of the final peptide andunder reaction conditions that will not alter the target peptide.

The side chain protecting groups for Tyr include tetrahydropyranyl,tert-butyl, trityl, benzyl, Cbz, Z-Br-Cbz, and 2,5-dichlorobenzyl. Theside chain protecting groups for Asp include benzyl, 2,6-dichlorobenzyl,methyl, ethyl, and cyclohexyl. The side chain protecting groups for Thrand Ser include acetyl, benzoyl, trityl, tetrahydropyranyl, benzyl,2,6-dichlorobenzyl, and Cbz. The side chain protecting groups for Thrand Ser are benzyl. The side chain protecting groups for Arg includenitro, Tosyl (Tos), Cbz, adamantyloxycarbonyl mesitoylsulfonyl (Mts), orBoc. The side chain protecting groups for Lys include Cbz,2-chlorobenzyloxycarbonyl (2-Cl-Cbz), 2-bromobenzyloxycarbonyl(2-BrCbz), Tos, or Boc.

After removal of the α-amino protecting group, the remaining protectedamino acids are coupled stepwise in the desired order. Each protectedamino acid is generally reacted in about a 3-fold excess using anappropriate carboxyl group activator such as2-(1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate(HBTU) or dicyclohexylcarbodiimide (DCC) in solution, for example, inmethylene chloride (CH2Cl2), dimethyl formamide (DMF) mixtures.

After the desired amino acid sequence has been completed, the desiredpeptide is decoupled from the resin support by treatment with a reagentsuch as trifluoroacetic acid (TFA) or hydrogen fluoride (HF), which notonly cleaves the peptide from the resin, but also cleaves all remainingside chain protecting groups. When the chloromethylated resin is used,hydrogen fluoride treatment results in the formation of the free peptideacids. When the benzhydrylamine resin is used, hydrogen fluoridetreatment results directly in the free peptide amide. Alternatively,when the chloromethylated resin is employed, the side chain protectedpeptide can be decoupled by treatment of the peptide resin with ammoniato give the desired side chain protected amide or with an alkylamine togive a side chain protected alkylamide or dialkylamide. Side chainprotection is then removed in the usual fashion by treatment withhydrogen fluoride to give the free amides, alkylamides, ordialkylamides.

In preparing the esters of the invention, the resins used to prepare thepeptide acids are employed, and the side chain protected peptide iscleaved with base and the appropriate alcohol, i.e., methanol. Sidechain protecting groups are then removed in the usual fashion bytreatment with hydrogen fluoride to obtain the desired ester. Thesesolid phase peptide synthesis procedures are well-known in the art andfurther described in Stewart, Solid Phase Peptide Syntheses (Freeman andCo., San Francisco, 1969).

These procedures can also be used to synthesize peptides in which aminoacids other than the 20 naturally occurring, genetically encoded aminoacids are substituted at one, two, or more positions of any of thecompounds of the invention. For instance, naphthylalanine can besubstituted for tryptophan, facilitating synthesis. Other syntheticamino acids that can be substituted into the peptides of the presentinvention include L-hydroxypropyl, L-3, 4-dihydroxyphenylalanyl, δ aminoacids such as L-δ-hydroxylysyl and D-δ-methylalanyl, L-α-methylalanyl, βamino acids, and isoquinolyl. D-amino acids and non-naturally occurringsynthetic amino acids can also be incorporated into the peptides of thepresent invention.

One can also modify the amino and/or carboxy terminus of the peptidecompounds of the invention to produce other compounds of the invention.Amino terminus modifications include methylating (i.e., --NHCH3 or--N(CH3)2), acetylating, adding a benzyloxycarbonyl (Cbz) group, orblocking the amino terminus with any blocking group containing acarboxylate functionality defined by RCOO or sulfonyl functionalitydefined by R-SO2--, where R is selected from the group consisting ofalkyl, aryl, heteroaryl, alkyl aryl, and the like, and similar groups.Carboxy terminus modifications include replacing the free acid with acarboxamide group or forming a cyclic lactam at the carboxy terminus tointroduce structural constraints. One can also cyclize the peptides ofthe invention, or incorporate a desamino or descarboxy residue at thetermini of the peptide, so that there is no terminal amino or carboxylgroup, to decrease susceptibility to proteases or to restrict theconformation of the peptide. C-terminal functional groups of thecompounds of the present invention include amide, amide lower alkyl,amide di(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lowerester derivatives thereof, and the pharmaceutically acceptable saltsthereof.

One can replace the naturally occurring side chains of the 20genetically encoded amino acids (or the stereoisomeric D amino acids)with other side chains, for instance with groups such as alkyl, loweralkyl, cyclic 4-, 5-, 6-, to 7-membered alkyl, amide, amide lower alkyl,amide di(lower alkyl), lower alkoxy, hydroxy, carboxy and the lowerester derivatives thereof, and with 4-, 5-, 6-, to 7-memberedheterocyclic. In particular, proline analogues in which the ring size ofthe proline residue is changed from 5 members to 4, 6, or 7 members canbe employed.

Cyclic groups can be saturated or unsaturated, and if unsaturated, canbe aromatic or non-aromatic. Heterocyclic groups preferably contain oneor more nitrogen, oxygen, and/or sulfur heteroatoms. Examples of suchgroups include the furazanyl, furyl, imidazolidinyl, imidazolyl,imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl (e.g. morpholino),oxazolyl, piperazinyl (e.g., 1-piperazinyl), piperidyl (e.g.,1-piperidyl, piperidino), pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl(e.g., 1-pyrrolidinyl), pyrrolinyl, pyrrolyl, thiadiazolyl, thiazolyl,thienyl, thiomorpholinyl (e.g., thiomorpholino), and triazolyl. Theseheterocyclic groups can be substituted or unsubstituted. Where a groupis substituted, the substituent can be alkyl, alkoxy, halogen, oxygen,or substituted or unsubstituted phenyl.

One can also readily modify peptides by phosphorylation, and othermethods for making peptide derivatives of the compounds of the presentinvention are described in Hruby et al., Jun. 1, 1990, Biochem J.268:249-262, incorporated herein by reference. Thus, the peptidecompounds of the invention also serve as structural models fornon-peptidic compounds with similar biological activity. Those of skillin the art recognize that a variety of techniques are available forconstructing compounds with the same or similar desired biologicalactivity as the lead peptide compound, but with more favorable activitythan the lead with respect to solubility, stability, and susceptibilityto hydrolysis and proteolysis. See, Morgan and Gainor, 1989, Ann. Rep.Med. Chem. 24:243-252, incorporated herein by reference. Thesetechniques include replacing the peptide backbone with a backbonecomposed of phosphonates, amidates, carbamates, sulfonamides, secondaryamines, and N-methylamino acids.

According to another preferred embodiment, residues X3 and X8 will beindependently selected from the group of C and Hoc. Thus, the compoundsof the present invention may exist in a cyclized form with anintramolecular disulfide bond. Alternatively, an intermoleculardisulfide bond can be produced to yield a dimeric compound. Theseintramolecular or intermolecular disulfide derivatives can berepresented schematically as shown below: ##STR1## wherein m and n areindependently 1 or 2.

Other embodiments of this invention provide for analogues of thesedisulfide derivatives in which one of the sulfurs has been replaced by aCH2 group or other isostere for sulfur. These analogues can be preparedfrom the compounds of the present invention wherein either X3 or X8 is Cor Hoc and the other is α-amino-γ-butyric acid, via an intramolecular orintermolecular displacement, using methods known in the art as shownbelow: ##STR2## wherein p is 1 or 2. One of skill in the art willreadily appreciate that this displacement can also occur using otherhomologs of α-amino-γ-butyric acid and homocysteine.

In addition to the foregoing cyclization strategies, other non-disulfidepeptide cyclization strategies can be employed. Such alternativecyclization strategies include, for example, amide-cyclizationstrategies as well as cyclization strategies involving the formation ofthio-ether bonds. Thus, the compounds of the present invention can existin a cyclized form with either an intramolecular amide bond or anintramolecular thio-ether bond. To illustrate the feasibility of theamidecyclization strategy, a peptide based on ggTYSCHFGPLTWVCKPQgg (SEQID NO:8) was synthesized wherein the first cysteine was replaced withlysine, the second cysteine was replaced with glutamic acid, and acyclic monomer was formed through an amide bond between the side chainsof these two residues. In addition, to illustrate the feasibility of thethio-ether cyclization strategy, a peptide based on ggTYSCHFGPLTWVCKPQgg(SEQ ID NO:8) was synthesized wherein the first cysteine was replacedwith lysine and a cyclic monomer was formed through a thio-ether linkagebetween the side chains of the lysine residue and the C-terminalcysteine. As such, in addition to disulfide cyclization strategies,amide-cyclization strategies and thio-ether cyclization strategies canboth be readily used to cyclize the compounds of the present invention.

Alternatively, the amino-terminus of the peptide can be capped with analpha-substituted acetic acid, wherein the alpha substituent is aleaving group, such as an α-haloacetic acid, for example, α-chloroaceticacid, α-bromoacetic acid, or α-iodoacetic acid. The compounds of thepresent invention wherein X3 is C or Hoc can be cyclized viadisplacement of the leaving group by the sulfur of the X3 residue. See,e.g., Barker et al. (1992) J. Med. Chem. 35:2040-2048 and Or et al.(1991) J. Org. Chem. 56:3146-3149, each of which is incorporated hereinby reference.

The compounds of the invention are useful in vitro as unique tools forunderstanding the biological role of EPO, including the evaluation ofthe many factors thought to influence, and be influenced by, theproduction of EPO and the binding of EPO to the EPO-R (e.g., themechanism of EPO signal transduction/receptor activation). The presentcompounds are also useful in the development of other compounds thatbind to the EPO-R, because the present compounds provide importantstructure-activity relationship (SAR) information that facilitate thatdevelopment.

Moreover, based on their ability to bind to the EPO receptor, thepeptides of the present invention can be used as reagents for detectingEPO receptors on living cells, fixed cells, in biological fluids, intissue homogenates, in purified, natural biological materials, etc. Forexample, by labelling such peptides, one can identify cells having EPO-Ron their surfaces. In addition, based on their ability to bind the EPOreceptor, the peptides of the present invention can be used in in situstaining, FACS (fluorescence-activated cell sorting), Western blotting,ELISA (enzyme-inked immunoadsoptive assay), etc. In addition, based ontheir ability to bind to the EPO receptor, the peptides of the presentinvention can be used in receptor purification, or in purifying cellsexpressing EPO receptors on the cell surface (or inside permeabilizedcells).

The compounds of the invention can also be utilized as commercialresearch reagents for various medical research and diagnostic uses. Suchuses can include but are not limited to: (1) use as a calibrationstandard for quantitating the activities of candidate EPO agonists in avariety of functional assays; (2) use as blocking reagents in randompeptide screening, i.e., in looking for new families of EPO receptorpeptide ligands, the peptides can be used to block recovery of thepresently claimed EPO peptides; (3) use in the co-crystallization withEPO receptor, i.e., the peptides of the present invention will allowformation of crystals bound to the EPO receptor, enabling thedetermination of receptor/peptide structure x-ray crystallography; (4)use to measure the capacity of erythrocyte precursor cells todifferentiate and thus, stimulate the induction of globin synthesis andincreases in the synthesis of the heme complex and in the number offerritin receptors; (5) use to maintain the proliferation and growth ofEPO-dependent cell lines, such as the FDCP-1-mEPO-R and the TF-1 celllines; and (6) other research and diagnostic applications wherein theEPO-receptor is preferably activated or such activation is convenientlycalibrated against a known quantity of an EPO agonist, and the like.

The compounds of the invention can also be administered to warm bloodedanimals, including humans, to simulate the binding of EPO to the EPO-Rin vivo. Thus, the present invention encompasses methods for therapeutictreatment of disorders associated with a deficiency of EPO that compriseadministering a compound of the invention in amounts sufficient tostimulate the EPO-R and thus, alleviate the symptoms associated with adeficiency of EPO in vivo. For example, the compounds of this inventionwill find use in the treatment of end-stage renal failure/dialysis;anemia associated with AIDS, anemia associated with chronic inflammatorydiseases (for example, rheumatoid arthritis and chronic bowelinflammation), autoimmune disease, and malignancies; and for boostingthe red blood count of a patient prior to surgery.

Other embodiments of this invention provide for the administration ofthe compounds of the invention for the treatment of disorders which arenot characterized by low or deficient red blood cells, for example as apretreatment prior to transfusions. In addition, administration of thecompounds of this invention can result in a decrease in bleeding timeand thus, will find use in the administration to patients prior tosurgery or for indications wherein bleeding is expected to occur. Inaddition, the compounds of this invention will find use in theactivation of megakaryoctes.

Since EPO has been shown to have a mitogenic and chemotactic effect onvascular endothelial cells as well as an effect on central cholinergicneurons (see, e.g., Amagnostou et al. (1990) Proc. Natl. Acad. Sci. USA87:5978-5982 and Konishi et al. (1993) Brain Res. 609:29-35), thecompounds of this invention will also find use for the treatment of avariety of vascular disorders, such as promoting wound healing, growthof collateral coronary blood vessels (such as those that may occur aftermyocardial infarction), trauma, and post-vascular graft treatment, and avariety of neurological disorders, generally characterized by lowabsolute levels of acetyl choline or low relative levels of acetylcholine as compared to other neuroactive substances e.g.,neurotransmitters.

Accordingly, the present invention includes pharmaceutical compositionscomprising, as an active ingredient, at least one of the peptides orother compounds of the invention in association with a pharmaceuticalcarrier or diluent. The compounds of this invention can be administeredby oral, parenteral (intramuscular, intraperitoneal, intravenous (IV) orsubcutaneous injection), transdermal (either passively or usingiontophoresis or electroporation), transmucosal (nasal, vaginal, rectal,or sublingual) routes of administration or using bioerodible inserts andcan be formulated in dosage forms appropriate for each route ofadministration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., lubricating, agents such as magnesium stearate. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering, agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, with the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions.

Examples of non-aqueous solvents or vehicles are propylene glycol,polyethylene glycol, vegetable oils, such as olive oil and corn oil,gelatin, and injectable organic esters such as ethyl oleate. Such dosageforms may also contain adjuvants such as preserving, wetting,emulsifying, and dispersing agents. They may be sterilized by, forexample, filtration through a bacteria retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured using sterile water, or some other sterile injectablemedium, immediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as cocoa butter or a suppository wax. Compositions fornasal or sublingual administration are also prepared with standardexcipients well known in the art.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment desired.Generally dosage levels of between 0.001 to 10 mg/kg of body weightdaily are administered to mammals.

As can be appreciated from the disclosure above, the present inventionhas a wide variety of applications. Accordingly, the following examplesare offered by way of illustration, not by way of limitation.

EXAMPLE 1 Solid Phase Peptide Synthesis

Various peptides of the invention were synthesized using the Merrifieldsolid phase synthesis techniques (see, Stewart, J. M., and Young, J. D.,Solid Phase Peptide Synthesis, 2d. edition (Pierce Chemical, Rockford,Ill., 1984)) on a Milligen/Biosearch 9600 automated instrument. Theresin used was PAL (Milligen/Biosearch), which is cross-linkedpolystyrene with 5-(4'-Fmoc-aminomethyl-3,5'-dimethoxyphenoxy) valericacid as a linker. Use of PAL resin results in a carboxyl terminal amidefunction upon cleavage of the peptide from the resin. Primary amineprotection on amino acids was achieved with F-moc, and side chainprotection groups were t-butyl for serine and tyrosine hydroxyls, tritylfor glutamine amides, and Pmc (2,2,5,7,8-pentamethylchroman sulfonate)for the arginine guanidino group. Each coupling was performed for eitherone or two hours with BOP (benzotriazolylN-oxtrisdimethylaminophosphonium hexafluorophosphate) and HOBt(1-hydroxybenztriazole).

In the synthesis of peptides with an amidated carboxy terminus, thefully assembled peptide was cleaved with a mixture of 90%trifluoroacetic acid, 5% ethanedithiol, and 5% water, initially at 4°C., and gradually increasing to room temperature over 1.5 hours. Thedeprotected product was filtered from the resin and precipitated withdiethyl ether. After thorough drying the product was purified by C18reverse phase high performance liquid chromatography with a gradient ofacetonitrile/water in 0.1% trifluoroacetic acid.

EXAMPLE 2 Bioassays

A. FDCP-1/mEPO-R

The FDCP-1/mEPO-R cells (10⁵) were grown to half stationary density inthe presence of growth factors (2.5 nm EPO). The cells were washed twicein PBS and then starved for 24 hours in whole media minus growthfactors.

Cell viability was determined by trypan blue staining. Stock in wholemedia minus growth factors was made to give desired number of cells per50 μl. The compounds to be tested were diluted 2-fold in 96 well tissueculture plate (50 μl per well final).

Cells (50 μl per well) were added to each well and incubated 24-48 hours(when the negative controls should die). Cell proliferation wasdetermined by MTT assay.

B. TF-1

The procedure set forth in Kitamura et al. (Blood 73:375-380 (1989),which is incorporated herein by reference) relating to the cell lineTF-1 having growth dependency on EPO was also conducted to demonstratethe activities of the compounds of the present invention as EPOagonists. Representative results are shown in FIG. 8. FIG. 8 depicts theeffects of EPO and the peptide VGNYMCHFGPITWVCRPGGG (SEQ ID NO:10) oncellular proliferation of the cell line TF-1.

C. Spleen Cell Proliferation

The procedure set forth in Krystal (Exp. Hematol. 11:649-660 (1983),which is incorporated herein by reference) for a microassay based on ³H-thymidine incorporation into spleen cells was also employed toascertain the ability of the compounds of the present invention to serveas EPO agonists. In brief, B6C3F1 mice were injected daily for two dayswith phenylhydrazine (60 mg/kg). On the third day, spleen cells wereremoved and their ability to proliferate over 24 hours using an MTTassay was ascertained. Photographs showing the proliferation ofrepresentative populations of spleen cells are shown in FIGS. 9A(control), 9B (treated with 500 pM EPO), and 9C (treated with 25 μmGGDYHCRMGPLTWVCKPLGG) (SEQ ID NO:9)at 200×magnification.

D. Cellular Proliferation: Peptide Dependent Growth of theEPO-Responsive Cell Line, FDC-P1/ER

1. Materials and Method

a. Sample Preparation: Peptides were resuspended in DMSO as a 1×10⁻² Mstock solution and serially diluted in 10-fold increments to generatethe following 100×solutions:

    1×10.sup.-3 1×10.sup.4 1×10.sup.-5 1×10.sup.4 1×10.sup.-7 1×10.sup.-8

Two μl of each stock dilution was added to a cell well as describedbelow in a total volume of 200 μl to generate final concentrations asfollows:

    1×10.sup.-5 1×10.sup.4 1×10.sup.-7 1×10.sup.4 1×10.sup.4 1×10.sup.-10

b. Cell Proliferation Assay:

i. Cell source: FDC-P1/ER, (Dexter, et al., J. Exp. Med. (1980)152:1036-1047, which is incorporated herein by reference), is a wellcharacterized nontransformed murine bone marrow derived cell line inwhich the erythropoietin receptor has been stably transfected. Cellsexhibit EPO dependent proliferation.

c. Experimental Protocol: Cells maintained in RPMI 1640/10% Fetal BovineSerum/antibiotics and 10 U/ml erythropoietin are grown to stationaryphase. Cells are harvested and resuspended in fresh medium withoutgrowth factor (erythropoietin) for 24 hr. Cells are counted andresuspended at a concentration of 800,000 cells/ml. Approximately fortythousand cells (50μ) are added to each well of a 96 well microtiterplate. Peptide is added to each well in triplicate. A standard doseresponse determination is run with each series of peptides. After aforty-two hr incubation (≈2 doubling), each well is pulsed with 1μCi/well Thymidine. Cells are incubated an additional six hr at whichtime cells are harvested and counted to assess thymidine incorporationas an indicator of cell proliferation.

d. Results: Peptides are evaluated on both the erythropoietin receptorcell line and the parental nonreceptor bearing cell line. In most cases,the peptide has been evaluated on a truncated human erythropoietinreceptor cell line. Results are expressed as the amount of peptidenecessary to yield one half of the maximal activity obtained withrecombinant erythropoietin. Representative results are reported intabular form with the relative binding data (See, Tables 17-21, infra).

E. Tyrosine Phosphorylation: Peptide Induced Tyrosine Phosphorylation ofErythropoietin Receptor and Intracellular Proteins

1. Materials and Method

a. Sample preparation: Peptide was resuspended in DMSO to yield aconcentrate of 1×10⁻² M.

b. Experimental Protocol: FDC-P1/muER cells maintained in RPMI 1640/10%Fetal Bovine Serum/antibiotics and 10 U/ml erythropoietin are grown tostationary phase. Cells are harvested and resuspended in fresh mediumwithout growth factor (erythropoietin) for 24 hr. Cells are counted andresuspended at a concentration of 500,000 cells/ml. One milliliter ofcells (500,000) are placed in an eppendorf tube. One microliter of a1×10⁻³ peptide solution is added to the cells (final concentration1×10⁻⁵ M) and allowed to incubate for 10 minutes at 37° C. Anerythropoietin control (final concentration 10 U/ml) was run with eachassay. Cells are collected by centrifugation at 14,000 rpm 4° C. Cellsare resuspended in 100 μl of SDS lysis buffer and subjected to SDSpolyacrylamide gel electrophoresis. The gel is transferred tonitrocellulose and probed with an anti-phosphotyrosine antibody (UpstateBiotechnology Incorporated) diluted 1:1000 for 1 hour. The membrane iswashed with Tris buffered saline and reprobed with an anti-mouseperoxidase labeled antibody. Reactive proteins are visualized using theECL western blotting reagents (Amersham).

c. Results: Erythropoietin binding to its receptor in anerythropoietin-responsive cell line induces tyrosine phosphorylation ofboth the receptor and numerous intracellular proteins, including Shc,vav and JAK2 kinase. Numerous peptides, including GGTYSCHFGPLTWVCKPQGG(SEQ ID NO:8), have been analyzed to assess their ability to mimic theresponse seen with erythropoietin. Active peptides, as judged by bindingand proliferation criteria, elicit an identical phosphorylation patternas that of erythropoietin in erythropoietin-responsive cells. Theseresults implicate that active peptides elicit their response through anerythropoietin-induced signal transduction pathway. Results are reportedin tabular form with the binding and proliferation data (See, Tables17-21, infra).

F. Cellular response kinetics: Peptide-Induced Initiation of Cell CycleMeasured By DNA Content

1. Experimental Protocol: FDCP-1/muER cells were grown to stationeryphase ≈3.0×10⁶ cells/ml. The cells were collected and resuspended infresh medium in the absence of factor and allowed to grow for anadditional 18 hr at which point the cells were divided into three flasksof equal cell density: -factor, +EPO and +peptide. Cells were thenstimulated with either 10 U/ml EPO or 10 μM peptide. Three million cellswere collected at the following time points: 0, 6, 8, 10, and 12 hr.(see, FIG. 15). Cells were washed twice in cold PBS and fixed byresuspending the cell pellet in 100 μl of cold PBS followed by 900 μl ofcold 70% ethanol. Cells were stained with 50 μg/ml of propidium iodineand fluorescence was measured on FACS Scan Flow cytometer. Thepercentage of cells in each phase was measured using the SOBR model ofCellFIT software, by Becton Dickinson.

Erythropoietin (10 U/ml) and GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) (1×10⁻⁵M) are equally effective at progressing cells through the cell cycle. Byten hours postinduction by either erythropoietin or peptide,approximately 45% of cells are in S phase as compared to the mediumcontrol of 15%. This result suggests that the peptide is able to elicitits response with the same kinetics as recombinant erythropoietin.

G. Colony Assay: Murine Bone Marrow and Human Peripheral Blood ColonyAssay

1. Materials and Methods:

A ten milliliter sample of peripheral blood was obtained from a healthyindividual in a standard sterile heparin vacutainer tube. Murine bonemarrow was obtained from the femurs of approximately 10 mice perexperiment. All reagents were obtained from Stem Cell Technologies Inc.(Vancouver, Canada).

a. Experimental Protocol: Briefly, a nucleated cell count was performedto establish the number and concentration of nucleated cells in theoriginal sample. In the case of peripheral blood, the sample issubjected to centrifugation through a Ficoll-Hypaque (1.077 g per ml)gradient at 400 g for 30 minutes at room temperature. Mononuclear cellsat the interface of the Ficoll-Hypaque solution are carefully removedand diluted to a total volume of about 10 ml. The cells obtained frommurine bone marrow or human peripheral blood were collected bycentrifugation and the supernatant was decanted. The pelleted cells wereresuspended in fresh medium and subjected to collection as describedabove. The washed cells were diluted in Iscove's medium/2% fetal bovineserum to the following concentration for plating:

Normal marrow: 1×10⁵ light density cells

Normal blood: 4×10⁵ light density cells

Cells were added to methyl cellulose per directions of the manufacturer.Peptides were assayed at the following final concentrations: 1×10⁻⁶ and1×10⁻⁵ M in a "minus EPO" methylcellulose medium. Equivalent cellnumbers were plated in "Complete" methylcellulose medium to assessmaximal colony formation. A control plate was run with each assay minusEPO and peptide to determine background colony formation. Colonies werescored after both 10 days and 18 days of incubation.

b. Results: As shown in Tables 13-15, GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)was able to promote colony formation, albeit at significantly lowerlevels as compared to that obtained on "Complete" methylcellulose medium(Erythropoietin 3 U/ml), in both murine bone marrow and human peripheralblood.

                  TABLE 13                                                        ______________________________________                                        COLONY ASSAY ON A HUMAN PERIPHERAL BLOOD                                      SPECIMEN (DONOR: MALE) (SET UP DATE: 2/10/94)                                 DATE  SAMPLE      CFU-E   MBFU-E PBFU-E CFU-GM                                ______________________________________                                        2/23/94                                                                             ZERO        X       X      X      X                                           DMSO        X       X      X      X                                           EPO (METHO- 11      25     X      X                                           CULT)                                                                         EPO (3 U/ml)                                                                               7      7      X      X                                           AFFY 244 10.sup.-5 M                                                                      10      5      X      X                                           AFFY 244 10.sup.-6 M                                                                      11      5      X      X                                     3/4/94                                                                              ZERO        X       X      X      X                                           DMSO        X       X      X      X                                           EFO (METHO-  1      11     13     9                                           CULT)                                                                         EFO (3 U/ml)                                                                               4      7      7      3                                           AFFY 244 10.sup.-5 M                                                                       7      9      2      4                                           AFFY 244 10.sup.-6 M                                                                       6      11     1      2                                     ______________________________________                                         CFU-E: COLONYFORMING UNITERYTHROID (1-2 CLUSTERS)                             MBFUE: MATURE BURSTFORMING UNITERYTHROID (3-8 CLUSTERS)                       PBRUE: PRIMITIVE BURSTFORMING UNITERYTHROID (9 OR MORE)                       CFUGM: COLONYFORMING UNIT GRANULOCYTIC/MONOCYTE/MACROPHAGE               

                  TABLE 14                                                        ______________________________________                                        Colony-Forming Cell Numbers (Murine Bone Marrow)                              1/28/94                                                                                          AFFY11157/AFFY 244                                         Progenitor                                                                              Control   EPO      10.sup.-5 M                                                                          10.sup.-6 M                               ______________________________________                                        2/10/94                                                                       CFU-E     0         23       2      3                                         BFU-E     0         5        0      0                                         CFU-GM    0         3        0      0                                         2/21/94                                                                       CFU-E     0         0        0      0                                         BFU-E     0         30       2      4                                         CFU-GM    0         3        0      0                                         ______________________________________                                         AFFY11157 = ggTYSCHFGPLTWVCKPQgg (SEQ ID NO:8)                           

                  TABLE 15                                                        ______________________________________                                        Colony-Forming Cell Numbers (Murine Bone Marrow)                              2/21/94                                                                                          AFFY11157/AFFY 244                                         Progenitor                                                                              Control   EPO      10.sup.-5 M                                                                          10.sup.-6 M                               ______________________________________                                        3/1/94                                                                        CFU-E     0         3        9      0                                         BFU-E     0         3        12     0                                         CFU-GM    0         >10      0      0                                         3/14/94                                                                       CFU-E     0         0        1      0                                         PBFU-E    0         10       8      0                                         MBFU-E    0         0        4      0                                         CFU-GM    0         26       0      0                                         ______________________________________                                    

H. Peptide-Induced Proliferation: Peptide-Dependent Growth on Cell LinesNot Responsive to Erythropoietin

a. Experimental protocol: Peptides were assayed as described in SectionD, supra. A growth curve was performed on each cell line using therelevant mitogen/growth factor for each cell line to assess growthpotential.

b. Results: As shown in Table 16, GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) wasunable to stimulate a growth response on non-erythropoietin responsivecell lines including both hematopoietic and non-hematopoietic celllines.

                  TABLE 16                                                        ______________________________________                                        Cell Proliferation Assays with 61233                                          Cell type                                                                              Species EPO    61233 Growth factor response                          ______________________________________                                        hematopoietic                                                                 TF-1     human   +      +     GM-CSF, IL3 (erythroid)                         M-07E    human   -      -     GM-CSF, IL3                                                                   (megakaryoblastic)                              AML193   human   -      -     GM-CSF, G-CSF, IL3                                                            (monocytic)                                     T-cell clone                                                                           human   ND     -     IL2                                             osteoblastic                                                                  TE85     human   -      -     serum                                           MC3T3    murine  -      -     serum                                           breast cell                                                                            human   ND     -     progestin                                       T47D                                                                          ______________________________________                                    

I. Immobilized EBP Based [¹²⁵ I]EPO Competition Binding Assay.

The extracellular domain of the human erythropoietin receptor (EPObinding protein, EBP) has been expressed and overproduced in E. coli. Aswith many other recombinant eukaryotic proteins used in E. coli, theprotein appeared as an insoluble product in laboratory scalefermentations and was refolded and purified to obtain active protein.EBP as produced by this method contains one free sulfhydryl group whichcan be modified without effecting the solution phase binding of ligand.In order to immobilize the EBP for equilibrium binding analysis and asthe basis for a competition binding assay, this observation was extendedfor the covalent attachment of EBP to agarose beads. The iodoacetylactivation chemistry of Sufolink beads (Pierce Chemical Co, Rockford,Ill.) is specific for free thiols and assures that the linkage is noteasily reversible. EBP-Sulfolink beads were made as follows: SulfoLinkgel suspension (10 ml) was mixed with coupling buffer (40 ml: 50 mMTris, pH 8.3, 5 mM EDTA) and the gel was allowed to settle. Thesupernatant was removed and the EBP (0.3-1 mg/ml in coupling buffer) tobe bound was added directly to the washed beads. The mixture was rockedgently for 30 minutes at room temperature, and the beads were allowed tosettle for 1 hour at room temperature. The supernatant was removed andretained, and the beads were washed twice with 20 ml of coupling buffer.The washes were recovered as well. The beads were then treated with 20ml of 0.05 M cysteine for 30 minutes at room temperature to blockunbound sites. Finally, the beads were washed with 50 ml of 1 M NaCl,then with 30 ml of PBS, and resuspended in 20 ml of PBS and stored at 4°C. for later use. The amount of EBP which was covalently bound to thebeads was determined by comparing the OD280 of the original EBP solutionto the total OD280 recovered in the reaction supernatant and the two 20ml washes. Typically, 40-60% of the applied EBP remains associated withthe beads.

Binding assays were initiated by the addition of EBP beads (50 μl) toindividual reaction tubes. Total binding was measured in tubescontaining 0.3-30 nM ¹²⁵ I-EPO (NEN Research Products, Boston Mass., 100μCi/μg). For determination of non-specific binding, unlabelled EPO wasadded at a level of 1000 fold in excess of the corresponding [¹²⁵ I]EPOconcentration. Each reaction volume was brought to 500 μl with bindingbuffer (PBS/0.2% BSA). The tubes were incubated for five hours (a timeperiod experimentally determined as adequate for the establishment ofequilibrium) at room temperature with gentle rocking. After five hours,each reaction mixture was passed through a 1 ml pipet tip plugged withglass wool. The tubes were washed with 1 ml wash buffer (PBS/5% BSA) andthis volume, as well as 2 additional 1 ml washes, were passed throughthe pipet tip and collected for determination of the free EPOconcentration. Equilibrium binding analysis of the specific associationof [¹²⁵ 1]EPO with EBP immobilized on these agarose beads indicates a Kdof 5 nM±2 based on a linear transformation (Scatchard) of the bindingisotherm (see, FIG. 16).

Competitive binding analysis assays of candidate peptides were performedas outlined below. Individual peptides were dissolved in DMSO to preparea stock solution of 1 mM. All reaction tubes (in duplicate) contained 50μL of EBP beads, 0.5 nM [¹²⁵ I]EPO and 0-500 μM peptide in a total of500 μL binding buffer. The final concentration of DMSO was adjusted to2.5% in all assay tubes, a value without detectable effect since anexamination of the sensitivity of the assay to DMSO demonstrated thatconcentrations of up to 25% DMSO (V/V) had no deleterious effect onbinding. Non-specific binding was measured in each individual assay byinclusion of tubes containing a large excess of unlabelled EPO (1000nM). Initial assay points with no added peptide were included in eachassay to determine total binding. Binding mixtures were incubatedovernight at room temperature with gentle rocking. The beads were thencollected using Micro-columns (Isolab, Inc., Akron, Ohio) and washedwith 3 mL of wash buffer. The columns containing the washed beads wereplaced in 12×75 mm glass tubes and bound radioactivity levels weredetermined using a gamma counter. The amount of bound [¹²⁵ I]EPO wasexpressed as a percentage of the control (total=100%) binding andplotted versus the peptide concentration after correction fornon-specific binding. The IC50 was defined as the concentration ofpeptide which reduced the binding of [¹²⁵ I]EPO to the EBP beads by 50%.All data are reported as relative to GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8)(RWJ61233) which demonstrated an IC50 of 5 μM (see, Tables 17-21,infra).

                                      TABLE 17                                    __________________________________________________________________________    GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) Substitution Series                        SEQ ID                  Relative                                              NO: RWJ NO.                                                                            Sequence       Binding.sup.†                                                               EPO-ED.sub.50 (μM)                                                                 Phosphorylation.sup.1                    __________________________________________________________________________     3  61233.sup.‡                                                             GGTYSCHFGPLTWVCKPQGG                                                                         1    0.1     +                                         52 61231                                                                              GGTASCHFGPLTWVCKPQGG                                                                         24   IA      -                                        189 61520                                                                              GGTTSCHFGPLTWVCKPQGG                                                                         24   IA      -                                        190 61598                                                                              GGTFSCHFGPLTWVCKPQGG                                                                         12   IA      -                                        191 61277                                                                              GGTYSCHFGALTWVCKPQGG                                                                         2    0.1     +                                        192 61278                                                                              GGTYSCHFGPLAWVCKPQGG                                                                         18   IA      -                                        193 61313                                                                              GGTYSCHFAPLTWVCKPQGG                                                                         16   IA      -                                        194 61314                                                                              GGTYSCHFGPATWVCKPQGG                                                                         1     .2     +                                        195 61395                                                                              GGTYSCHFGPLTAVCKPQGG                                                                         >100 IA      -                                        196 62145                                                                              GGTYSCHFGPLTFVCKPQGG                                                                         6     0.25                                            244 61530                                                                              GGTYSC-FGPLTWVCKPQGG                                                                         40   IA      -                                        __________________________________________________________________________     *Amount required to achieve the half maximal level of EPO dependent           proliferation (11 pM)                                                         .sup.1 Assayed at 10 μM                                                    .sup.2 IA = inactive                                                          .sup.† Binding relative to RWJ61233                                    .sup.‡ Note that all peptides are cyclic (except 61394) and        were analyzed as COOH terminal amides (--CONH.sub.2)                          61233 = AFFY11157 = AF11157 = AFFY 244                                   

                                      TABLE 18                                    __________________________________________________________________________    GGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) Truncation Series                          SEQ ID                  Relative                                              NO: RWJ NO.                                                                            Sequence       Binding.sup.†                                                               EPO-ED.sub.50 (μM)                                                                 Phosphorylation.sup.1                    __________________________________________________________________________     8  61233.sup.‡                                                             GGTYSCHFGPLTWVCKPQGG                                                                         1    0.1     +                                         13 61596                                                                              GGTYSCHFGPLTWVCKPQ                                                                           1.6  0.08    +                                        245 61597                                                                              TYSCHFGPLTWVCKPQGG                                                                           8    2       +                                        197 61230                                                                              TYSCHFGPLTWVCKPQ                                                                             6    2       +                                        198 61232                                                                              YSCHFGPLTWVCKP 9    20      +/-                                       16 61279                                                                              YSCHFGPLTWVCK  14   3       +/-                                      246 61477                                                                              YSCHFGPLTWVC   50   IA.sup.2                                                                              -                                        199 61895                                                                              YSCHFGALTWVCK  32   IA                                                17 61513                                                                              Y-CHFGPLTWVC   12   2       +                                        200 61177                                                                              SCHFGPLTWVCK   18   IA      -                                         19 AF11154                                                                            GGCRIGPITWVCGG 13   IA      -                                        201 61394                                                                              HFGPLTWV       >100 IA      -                                        __________________________________________________________________________     *Amount required to achieve the half maximal level of EPO dependent           proliferation (11 pM)                                                         .sup.1 Assayed at 10 μM                                                    .sup.2 IA = inactive                                                          .sup.† Binding relative to RWJ61233                                    .sup.‡ Note that all peptides are cyclic (except 61394) and        were analyzed as COOH terminal amides (--CONH.sub.2)                          61233 = AFFY11157 = AF11157 = AFFY244                                    

                                      TABLE 19                                    __________________________________________________________________________    Sequence Analog Peptides                                                                                Relative                                            SEQ ID NO:                                                                          RWJ No.                                                                            Sequence       Binding.sup.‡                                                           EPO-ED.sub.50 (μM)                                                                 Phosphorylation.sup.1                  __________________________________________________________________________     8    61233.sup.‡                                                             GGTYSCHFGPLTWVCKPQGG                                                                         1    0.1     +                                      202   61721                                                                              1 #STR3##      >100 IA.sup.2                                       14    61718                                                                              GGLYACHMGPMTWVCQPLRG                                                                         0.6  0.1                                            57    61719                                                                              GGEYLCRMGPMTWVCTPVGG                                                                         8    9                                              59    61720                                                                              GGLYTCRMGPITWVCLPAGG                                                                         ND   --                                             53    61717                                                                              GGNYYCRFGPITFECHPTGG                                                                         >100 (S1)                                                                          IA                                             __________________________________________________________________________     Amount required to achieve the half maximal level of EPO dependent            proliferation (11 pM)                                                         .sup.1 Assayed at 10 μM; .sup.2 IA = inactive                              .sup.‡ Binding relative to RWJ61233                                .sup.‡ Note that all peptides are cyclic (except 61394) and        were analyzed as COOH terminal amides (--CONH.sub.2)                          61233 = AFFY11157 = AF11157 = AFFY244                                    

                                      TABLE 20                                    __________________________________________________________________________    Position #4 Substitution Series                                                                                       EPO-ED.sub.50 (μM)*                SEQ ID                                                                            RWJ                                        truncated human                NO: No. (X)     Sequence       Relative Binding .sup.‡                                                     murine receptor                                                                      receptor                       __________________________________________________________________________     8  61233.sup.†                                                                        GGTYSCHFGPLTWVCKPQGG                                                                          1       0.1    0.1                             52 61231       GGTASCHFGPLTWVCKPQGG                                                                         24       1A.sup.2                              189 61520       GGTTSCHFGPLTWVCKPQGG                                                                         24       IA                                    190 61598       GGTFSCHFGPLTWVCKPQGG                                                                         12       IA                                    247 61894                                                                             p-NO.sub.2 -Phe                                                                       GGTXSCHFGPLTWVCKPQGG                                                                         17       IA     0.8                            248 62019                                                                             p-NH.sub.2 -Phe                                                                       GGTXSCHFGPLTWVCKPQGG                                                                         18       IA     3.0                            249 62020                                                                             p-F-Phe GGTXSCHFGPLTWVCKPQGG                                                                          8       1.0    0.1                            250 62021                                                                             3,5-dibromo-tyr                                                                       GGTXSCHFGPLTWVCKPQGG                                                                         30       IA     IA                             __________________________________________________________________________     *Amount required to achieve the half maximal level of EPO dependent           proliferation (11 pM)                                                         .sup.1 ND = Not determined                                                    .sup.2 IA = Inactive                                                          .sup.‡ Binding relative to RWJ61233                                Note that all peptides are cyclic and were analyzed as COOH terminal          amides (--CONH.sub.2)                                                         61233 = AFFY11157 = AF11157 = AFFY244                                    

                                      TABLE 21                                    __________________________________________________________________________    Differential Activity Series-GGTYSCHFGPLTWVCKPQGG (SEQ                        ID NO:8) Based                                                                                               EPO-ED.sub.50 (μM)*                                                            truncated                                  SEQ ID                    Relative                                                                           murine                                                                            human                                      NO:*                                                                              RWJ No.                                                                             Sequence        Binding .sup.‡                                                          receptor                                                                          receptor                                   __________________________________________________________________________     8  61233*                                                                              GGTYSCHFGPLTWVCKPQGG                                                                          1    0.1 0.1                                         13 61596 GGTYSCHFGPLTWVCKPQ                                                                            1.6  0.08                                                                              0.02                                        14 61718 GGLYACHMGPMTWVCQPLRG                                                                          0.6  0.1 0.08                                        14 AF11288                                                                             GGLYACHMGPMTWVCQPLRG                                                                          0.2  0.15                                                                              ND.sup.1                                    21 61757 (H22)                                                                         LGRKYSCHFGPLTWVCQPAKKD                                                                        1    0.11                                                                              0.15                                        15 AF11654                                                                             TIAQYICYMGPETWECRPSPKA                                                                        1    0.2 0.02                                       251 62145 GGTYSCHFGPLTFVCKPQGG                                                                          6    0.25                                                                              0.5                                         18 62146 Ac-GGTYSCHFGPLTWVCKPQGG                                                                       4    0.03                                                                              0.06                                       247 61894 GGTXSCHFGPLTWVCKPQGG                                                                          17   IA.sup.2                                                                          0.8                                                  p-NO.sub.2 -Phe                                                     248 62019 GGTXSCHFGPLTWVCKPQGG                                                                          18   IA  3.0                                                  p-NH.sub.2 -Phe                                                     249 62020 GGTXSCHFGPLTWVCKPQGG                                                                          8    1.0 0.1                                                  p-F-Phe                                                             __________________________________________________________________________     *Amount required to achieve the half maximal level of EPO dependent           proliferation (11 pM)                                                         .sup.1 ND = Not determined                                                    .sup.2 IA = Inactive                                                          .sup.‡ Binding relative to RWJ61233                                Note that all peptides are cyclic and were analyzed as COOH terminal          amides (--CONH.sub.2)                                                         61233 = AFFY11157 = AF11157 = AFFY244                                    

J. Polycythemic Exhypoxic Mouse Bioassay

Female BDF1 mice (18-20 gms) are subjected to a conditioning cycle (inhypobaric chambers) of 18 hrs. at 0.40±0.02 atm. and 6 hrs. at ambientpressure for a period of 14 days.

Mice are maintained at ambient pressure for 72 hrs prior toadministration of r-HuEPO or test samples. Test samples or r-HuEPOstandard are diluted for injection into conditioned mice. The vehicleconsists of: PBS containing 0.1% BSA (w/v). For each dilution, 0.5 ml isadministered subcutaneously into each of 10 mice. ⁵⁹ Fe is administered48 hrs. later. Blood samples are taken 48 hrs. following administrationof ⁵⁹ Fe. Hematocrits and radioactivity measurements are determined foreach sample. Dose range and results (two different assays) are set forthin Table 22 and FIGS. 17A-17C, infra.

                  TABKE 22                                                        ______________________________________                                                  DOSE     n     LOG MEAN                                             ______________________________________                                        EPO St.     0.000 U    10    0.26                                                         0.025      10    1.65                                                         0.050      10    2.74                                                         0.100      10    3.28                                             DMSO        1.40%      7     0.58                                                         0.35%      5     0.60                                             244-1       0.25 μg 7     0.62                                                         0.50       8     0.76                                                         1.00       9     0.92                                             244-2       2.00       9     1.38                                                         4.00       10    1.81                                                         8.00       9     2.26                                             244-3       14.0       10    2.44                                                         28.0       10    3.15                                                         56.0       9     3.16                                             0.1 mg AFFY244 ≈ 1 U r-HuEPO (8.3 ng)                                 ______________________________________                                    

In addition, using the foregoing polycythemic exhypoxic mouse bioassay,TIAQYICYMGPETWECRPSPKA (SEQ ID NO:15) an a dimeric peptide analog ofGGTYSCHFGPLTWVCKPQGG (SEQ ID NO:8) containing two disulfide bonds(AF12080) were tested. The results of the polycythemic exhypoxic mousebioassay are set forth in FIGS. 18A-18B. In addition, Table 23, infra,sets forth the approximate equivalency of EPO and various mimeticpeptides.

                  TABLE 23                                                        ______________________________________                                                                    Amount of Peptide                                 SEQ ID                      Equivalent to 0.025                               NO:   Peptide               units of EPO (nmol)                               ______________________________________                                         8    GGTYSCHFGPLTWVCKPQGG  3.8                                                     (RWJ 61233/AFFY11157)                                                   13    GGTYSCHFGPLTWVCKPQ    0.5                                                     (RWJ 61596)                                                             21    LGRKYSCHFGPLTWVCQPAKKD                                                                              3.1                                                     (RWJ 61757)                                                             15    TIAQYICYMGPETWECRPSPKA                                                                              11-21                                                   (AFFY11654)                                                              8    GGTYSCHFGPLTWVCKPQGG Dimer                                                                          0.035                                                   (AFFY12080)                                                             ______________________________________                                    

K. Reticulocyte Assay

Normal untreated female BDF1 mice are dosed (0.5 ml, S.Q.) on threeconsecutive days with either EPO or experimental compound. The vehicle:PBS, 10% PEG 8000, 0.25% BSA, with DMSO being added. At day three, miceare also dosed (0.1 ml, I.P.) with iron dextran (100 mg/ml). At dayfive, mice are anesthetized with CO2 and bled by cardiac puncture. %reticulocytes is determined by thiazole orange staining and flowcytometer analysis (retic-count program). Hematocrits are manuallydetermined. The percent of corrected reticulocytes is determined usingthe following formula:

% RETIC(CORRECTED)=% RETIC.(OBSERVED) X Hct.(INDIVIDUAL)/Hct.(NORMAL).The results obtained using the foregoing reticulocyte assay are setforth in FIGS. 18A-18B and FIGS. 19A-19B.

It is to be understood that the above description is intended to beillustrative and not restrictive. Many embodiments will be apparent tothose of skill in the art upon reviewing the above description. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled. The disclosures of allarticles and references, including patent publications, are incorporatedherein by reference.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 259                                           - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 1 or position 10 is Cys or                                    homocysteine - #"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa = Arg, His, Leu, or                                                             Trp"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                    #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 1 or position 10 is Cys or                                    homocysteine - #"                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 -      Xaa Xaa Xaa Gly Pro Xaa Thr Trp - # Xaa Xaa                            #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 3 or position 12 is Cys or                                    homocysteine - #"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa = Arg, His, Leu, or                                                             Trp"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 3 or position 12 is Cys or                                    homocysteine - #"                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 -      Tyr Xaa Xaa Xaa Xaa Gly Pro Xaa - # Thr Trp Xaa Xaa                    #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 4 or position 13 is Cys or                                    homocysteine - #"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Arg, His, Leu, or                                                             Trp"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 13                                                    #/note= "Xaa = Cys, Ala,RMATION:                                                             alpha-amino- - #gamma-bromobutyric acid,                                      or homocy - #steine, provided that either Xaa                                 in positi - #on 4 or position 13 is Cys or                                    homocysteine - #"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa = any amino acid"N:                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 -      Xaa Tyr Xaa Xaa Xaa Xaa Gly Pro - # Xaa Thr Trp Xaa Xaa Xaa Xaa        Xaa                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Arg, His, Leu, or                                                             Trp"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa = any amino acid"N:                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 -      Xaa Tyr Xaa Cys Xaa Xaa Gly Pro - # Xaa Thr Trp Xaa Cys Xaa Xaa        Xaa                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Arg or His"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = Phe or Met"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = Ile, Leu, Thr, Met,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Asp or Val"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa = Gly, Lys, Leu, Gln,                                                           Arg, Ser, - # or Thr"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa = Ala, Gly, Pro, Arg,                                                           or Tyr"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa = any amino acid"N:                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 -      Xaa Tyr Xaa Cys Xaa Xaa Gly Pro - # Xaa Thr Trp Xaa Cys Xaa Xaa        Xaa                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = Asp, Glu, Leu, Asn,                                                           Ser, Thr, - # or Val"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = Ala, His, Lys, Leu,                                                           Met, Ser, - # or Thr"                                          -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Arg or His"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = Phe or Met"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = Ile, Leu, Thr, Met,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Asp or Val"ATION:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa = Lys, Arg, Ser, or                                                             Thr"                                                           -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa = any amino acid"N:                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 -      Xaa Tyr Xaa Cys Xaa Xaa Gly Pro - # Xaa Thr Trp Xaa Cys Xaa Pro        Xaa                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 -      Gly Gly Leu Tyr Leu Cys Arg Phe - # Gly Pro Val Thr Trp Asp Cys        Gly                                                                           #   15                                                                        -      Tyr Lys Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 -      Gly Gly Asp Tyr His Cys Arg Met - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Leu Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                -      Val Gly Asn Tyr Met Cys His Phe - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Gly Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                -      Gly Gly Val Tyr Ala Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Leu Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                -      Val Gly Asn Tyr Met Ala His Met - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Gly Gly                                                            - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln                                                                - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                -      Gly Gly Leu Tyr Ala Cys His Met - # Gly Pro Met Thr Trp Val Cys        Gln                                                                           #   15                                                                        -      Pro Leu Arg Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                -      Thr Ile Ala Gln Tyr Ile Cys Tyr - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Arg Pro Ser Pro Lys Ala                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                -      Tyr Ser Cys His Phe Gly Pro Leu - # Thr Trp Val Cys Lys                #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                -      Tyr Cys His Phe Gly Pro Leu Thr - # Trp Val Cys                        #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/product= "OTHER"R INFORMATION:                                              #"Xaa = N-acetyl-glycine"                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                -      Xaa Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                -      Gly Gly Cys Arg Ile Gly Pro Ile - # Thr Trp Val Cys Gly Gly            #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly Ser Ser Lys                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                -      Leu Gly Arg Lys Tyr Ser Cys His - # Phe Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Gln Pro Ala Lys Lys Asp                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                -      Gly Gly Trp Val Thr Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Gly                                                                           #   15                                                                        -      Val His Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                -      Gly Gly Gln Leu Leu Cys Gly Ile - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Trp Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                -      Gly Gly Leu Tyr Leu Cys Arg Met - # Gly Pro Val Thr Trp Glu Cys        Gln                                                                           #   15                                                                        -      Pro Arg Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                -      Gly Gly Lys Tyr Ser Cys Phe Met - # Gly Pro Thr Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Val Gly Arg Gly Val                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                -      Gly Gly Trp Val Tyr Cys Arg Ile - # Gly Pro Ile Thr Trp Val Cys        Asp                                                                           #   15                                                                        -      Thr Asn Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                -      Gly Gly Ile Tyr Lys Cys Leu Met - # Gly Pro Leu Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Pro Asp Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                -      Gly Gly Met Tyr Tyr Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Gly Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                -      Gly Gly Thr Thr Gln Cys Trp Ile - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Ala Arg Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                -      Gly Gly Pro Tyr His Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Gly                                                                           #   15                                                                        -      Pro Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                -      Gly Gly Glu Tyr Leu Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Glu                                                                           #   15                                                                        -      Arg Tyr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                -      Gly Gly Glu Tyr Arg Cys Arg Met - # Gly Pro Ile Ser Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                -      Gly Gly Asn Tyr Thr Cys Arg Phe - # Gly Pro Leu Thr Trp Glu Cys        Thr                                                                           #   15                                                                        -      Pro Gln Gly Gly Gly Ala                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                -      Gly Gly Asn Tyr Val Cys Arg Met - # Gly Pro Ile Thr Trp Ile Cys        Thr                                                                           #   15                                                                        -      Pro Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                -      Gly Gly Ser Trp Asp Cys Arg Ile - # Gly Pro Ile Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Trp Ser Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                -      Gly Gly Asp Tyr Thr Cys Arg Met - # Gly Pro Met Thr Trp Ile Cys        Thr                                                                           #   15                                                                        -      Ala Thr Arg Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                -      Gly Gly Asp Tyr Asn Cys Arg Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Ser Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                -      Gly Gly Ser Tyr Leu Cys Arg Met - # Gly Pro Thr Thr Trp Leu Cys        Thr                                                                           #   15                                                                        -      Ala Gln Arg Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                -      Gly Gly Leu Tyr Leu Cys Arg Met - # Gly Pro Gln Thr Trp Met Cys        Gln                                                                           #   15                                                                        -      Pro Gly Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:40:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                -      Gly Gly Asp Tyr Val Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Ala                                                                           #   15                                                                        -      Pro Tyr Gly Arg                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:41:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                -      Gly Gly Leu Tyr Glu Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Gly Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:42:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                -      Gly Gly Trp Tyr Ser Cys Leu Met - # Gly Pro Met Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Ala His Arg Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:43:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                -      Gly Gly Lys Tyr Tyr Cys Trp Met - # Gly Pro Met Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:44:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                -      Gly Gly Tyr Val Met Cys Arg Ile - # Gly Pro Ile Thr Trp Val Cys        Asp                                                                           #   15                                                                        -      Ile Pro Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:45:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                -      Gly Ser Cys Leu Gln Cys Cys Ile - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      His Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:46:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                -      Gly Gly Asn Tyr Phe Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Gln                                                                           #   15                                                                        -      Arg Ser Val Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:47:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                -      Gly Gly Glu Tyr Ile Cys Arg Met - # Gly Pro Leu Thr Trp Glu Cys        Lys                                                                           #   15                                                                        -      Arg Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:48:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                -      Gly Gly Leu Tyr Ala Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Tyr Met Ala Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:49:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                -      Gly Gly Gln Tyr Leu Cys Thr Phe - # Gly Pro Ile Thr Trp Leu Cys        Arg                                                                           #   15                                                                        -      Gly Ala Gly Gly Gly Ser                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:50:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                -      Gly Gly Tyr Thr Thr Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Ala His Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:51:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                -      Gly Gly Thr Tyr Lys Cys Trp Met - # Gly Pro Met Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:52:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                -      Gly Gly Thr Ala Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:53:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                -      Gly Gly Asn Tyr Tyr Cys Arg Phe - # Gly Pro Ile Thr Phe Glu Cys        His                                                                           #   15                                                                        -      Pro Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:54:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                -      Gly Gly Leu Tyr Ala Cys His Met - # Gly Pro Met Thr Trp Val Cys        Gln                                                                           #   15                                                                        -      Pro Leu Arg Gly Gly Gly Ser                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:55:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                -      Gly Gly Glu Tyr Lys Cys Tyr Met - # Gly Pro Ile Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Glu Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:56:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                -      Gly Gly Asp Tyr Val Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Ala                                                                           #   15                                                                        -      Pro Tyr Gly Arg Gly Gly Ser                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:57:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                -      Gly Gly Glu Tyr Leu Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Pro Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:58:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                -      Gly Gly Ser Tyr Leu Cys Arg Met - # Gly Pro Thr Thr Trp Leu Cys        Thr                                                                           #   15                                                                        -      Ala Gln Arg Gly Gly Gly Asn                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:59:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                -      Gly Gly Leu Tyr Thr Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Leu                                                                           #   15                                                                        -      Pro Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:60:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                -      Gly Gly Leu Tyr Lys Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Phe Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:61:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                -      Gly Gly Pro His His Val Tyr Ala - # Cys Arg Met Gly Pro Leu Thr        Trp                                                                           #   15                                                                        -      Ile Cys                                                                - (2) INFORMATION FOR SEQ ID NO:62:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                -      Tyr Xaa Cys Arg Ile Gly Pro Ile - # Thr Trp Val Cys                    #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:63:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                -      Gly Gly Glu Tyr Ile Cys Val Met - # Gly Pro Asn Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Thr Arg Gly His Gly Ser                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:64:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                -      Gly Gly Glu Tyr Leu Cys Arg Met - # Gly Pro Met Thr Trp Val Ser        Pro                                                                           #   15                                                                        -      Phe Thr Arg Lys Gly Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:65:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                -      Gly Gly Gln Tyr Ile Cys Arg Phe - # Gly Pro Ile Thr Trp Gln Ser        Gln                                                                           #   15                                                                        -      Pro Ala Gly Gly Gly Ser                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:66:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                -      Gly Arg Glu Tyr Ser Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Met                                                                           #   15                                                                        -      Pro Arg Ala Ser Leu Gly Ser                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:67:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                -      Gly Asp Tyr Leu Cys Ser Met Gly - # Pro Ile Thr Trp Ile Cys Val        Pro                                                                           #   15                                                                        -      Glu Arg Gly Gly Gly Ser                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:68:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                -      Glu Leu Trp Tyr Ser Cys Arg Met - # Gly Pro Val Thr Trp Met Cys        Gly                                                                           #   15                                                                        -      Arg Tyr Gln Gly Gly Gly Ser                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:69:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                -      Gln Ile Cys Arg Ala Asp Arg Lys - # Gly Ile Tyr Gln Cys Trp Tyr        Gly                                                                           #   15                                                                        -      Pro Glu Thr Trp Ile Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:70:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                -      Gln Gln Gly Tyr Ser Leu Trp Leu - # Pro Trp Tyr Asn Cys Val Leu        Gly                                                                           #   15                                                                        -      Pro Tyr Thr Trp Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:71:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                -      Tyr Gly Gly Ser Ala Ala Val Pro - # Trp Lys Tyr Gly Cys Ser Leu        Gly                                                                           #   15                                                                        -      Pro Val Thr Trp Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:72:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                -      Gln Ile Val Ser Trp Gly Leu Tyr - # Ser Gly Tyr Leu Cys Met Val        Gly                                                                           #   15                                                                        -      Pro Val Thr Trp Leu Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:73:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                -      Gly Ser Gly Ala Leu Ser Ala Ala - # Gly Trp Tyr Gly Cys Arg Val        Gly                                                                           #   15                                                                        -      Pro Leu Thr Trp Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:74:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                -      Ser Val Val Ser His Asp Ala Ala - # Gly Val Tyr Asp Cys Val Ile        Gly                                                                           #   15                                                                        -      Pro Val Thr Trp Ile Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:75:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                -      Ile Tyr Ser Trp Thr Gly Ile Leu - # Gly Ser Tyr Val Cys Trp Tyr        Gly                                                                           #   15                                                                        -      Pro Asp Thr Trp Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:76:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                -      Ser Cys Ile Tyr Val Arg Phe Phe - # Tyr Cys Tyr Gln Cys Ser Glu        Gly                                                                           #   15                                                                        -      Pro Ala Thr Trp Leu Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:77:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                -      Thr Val Ala Lys Gly Gln Ser Gly - # Val Arg Tyr Ser Cys Leu Arg        Gly                                                                           #   15                                                                        -      Pro Glu Thr Trp Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:78:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                -      Val Gln Pro Gln Tyr Lys Trp Ala - # Thr Met Tyr Gln Cys Trp Lys        Gly                                                                           #   15                                                                        -      Pro Ser Thr Trp Phe Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:79:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                -      Lys Ser Gly Val Trp Glu Met Gly - # Ser Ser Tyr Gln Cys Ala Arg        Gly                                                                           #   15                                                                        -      Pro Arg Thr Trp Cys Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:80:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                -      Cys Ser Val Arg Arg Met Asp Arg - # Glu Tyr Tyr Arg Cys Cys Arg        Gly                                                                           #   15                                                                        -      Pro Phe Thr Trp Gln Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:81:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                -      Lys Tyr Gln Glu Glu Met Phe Met - # Gly Tyr Gln Cys Leu Gln Gly        Pro                                                                           #   15                                                                        -      Lys Thr Gln Leu Cys Gly Gly                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:82:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                -      Val Cys Pro Gly Ser Glu Phe Arg - # Val Gly Tyr Ile Cys Ala Met        Gly                                                                           #   15                                                                        -      Pro Tyr Thr Trp Asp Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:83:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                -      Ser Leu Cys Ser Ser Arg Cys Asn - # Ser Pro Tyr Phe Cys Ser Ile        Gly                                                                           #   15                                                                        -      Pro Ser Thr Trp Arg Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:84:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                -      Gln Ala Ser Leu Gly Leu Pro Leu - # Lys Gln Tyr Leu Cys Val Leu        Gly                                                                           #   15                                                                        -      Pro His Thr Trp Leu Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:85:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                -      Ala Cys Lys Pro Ala Ala Leu Phe - # Val Gln Tyr Gly Cys Val Leu        Gly                                                                           #   15                                                                        -      Pro Met Thr Trp Ile Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:86:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                -      Ser Cys Glu Arg Ala Gly Gly Arg - # Trp Glu Tyr Val Cys Gln Trp        Gly                                                                           #   15                                                                        -      Pro Asp Thr Trp Leu Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:87:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                -      Arg Val Ala Arg Gln Val Gln Gln - # Val Ser Tyr Trp Cys Ala His        Gly                                                                           #   15                                                                        -      Pro Ala Thr Cys Tyr Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:88:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                -      His Lys Tyr Asp Thr Leu Met Leu - # Thr Asn Tyr Val Cys Gln Arg        Gly                                                                           #   15                                                                        -      Pro Leu Thr Gln Leu Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:89:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                -      Gly Gly Tyr His Cys Glu Trp Gly - # Pro Glu Thr Trp Ile Cys Arg        Pro                                                                           #   15                                                                        -      Glu Ile Ser Pro Leu Thr Val Met - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:90:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                -      Gly Gly Tyr Ile Cys Asp Tyr Gly - # Pro Leu Thr Trp Ala Cys Lys        Pro                                                                           #   15                                                                        -      Ala Gly Ala Thr Leu Leu Gln Pro - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:91:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                -      Gly Gly Tyr Thr Cys Arg Phe Gly - # Pro Val Thr Trp Asp Cys Leu        Pro                                                                           #   15                                                                        -      Ala Ile Asn His Asn Gly Val Leu - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:92:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                -      Gly Gly Tyr Val Cys Asp Phe Gly - # Pro Thr Thr Trp Ile Cys Arg        Gly                                                                           #   15                                                                        -      Gln Val Met Glu His Ile Asn Thr - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:93:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                -      Gly Gly Tyr Met Cys Asn Met Gly - # Pro Leu Thr Trp Asp Cys Ser        Pro                                                                           #   15                                                                        -      Val Arg Ser Thr Ser Met Ala Trp - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:94:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                -      Gly Gly Tyr Asn Cys Thr Met Gly - # Pro Asn Thr Trp Val Cys Thr        Pro                                                                           #   15                                                                        -      Ala Ala Glu Ser Pro Ala Val Phe - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:95:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                -      Gly Gly Tyr Gly Cys Arg Ile Gly - # Pro Ile Thr Trp Ile Cys Asp        Asp                                                                           #   15                                                                        -      Val Ser Arg Ser Pro Arg Ala                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:96:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                -      Gly Gly Tyr Thr Cys Arg Met Gly - # Pro Gln Thr Trp Glu Cys Leu        Pro                                                                           #   15                                                                        -      Met Ser Glu Gly Val                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:97:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                -      Gly Gly Tyr Asn Cys Lys Phe Gly - # Pro Gln Thr Trp Asp Cys Ser        Ser                                                                           #   15                                                                        -      Ala Asn Leu Lys Glu Val                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:98:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                -      Gly Tyr Leu Cys Glu Met Gly Pro - # Glu Thr Trp Met Cys Arg Pro        Glu                                                                           #   15                                                                        -      Asp Ala Lys Leu Gly Val                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:99:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                -      Gly Gly Tyr Gly Cys Lys Phe Gly - # Pro Val Thr Trp Ile Cys Glu        Asp                                                                           #   15                                                                        -      Leu Leu Leu Asp Pro Met Tyr                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:100:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                               -      Gly Gly Tyr Asn Cys Lys Phe Gly - # Pro Gln Thr Trp Asp Cys Ser        Ser                                                                           #   15                                                                        -      Ala Asn Leu Lys Glu Val Leu Val                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:101:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                               -      Gly Tyr Leu Cys Glu Met Gly Pro - # Glu Thr Trp Met Cys Arg Pro        Glu                                                                           #   15                                                                        -      Asp Cys Glu Ala Trp                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:102:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                               -      Gly Gly Tyr Gly Cys Gly Leu Ala - # Pro Val Thr Trp Glu Cys Pro        Gln                                                                           #   15                                                                        -      Val Ser Ile Pro Tyr Gly Leu Ser - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:103:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                               -      Gly Gly Tyr Gly Cys Arg Ile Gly - # Pro Thr Thr Trp Ile Cys Asp        Ser                                                                           #   15                                                                        -      Thr Val Pro Gln Leu Arg Glu Val - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:104:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                               -      Gly Gly Tyr Arg Cys Ser Trp Ala - # Pro Glu Thr Trp Val Cys Asp        Asn                                                                           #   15                                                                        -      His Ser Ala                                                            - (2) INFORMATION FOR SEQ ID NO:105:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                               -      Gly Tyr Leu Cys Asn Phe Gly Pro - # Ile Thr Trp Asp Cys Val Ser        Ser                                                                           #   15                                                                        -      Ala Gln Ser Glu Met Gln Ile Gly - # Gly                                #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:106:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                               -      Gly Gly Ala Glu Leu Gln Tyr Cys - # Lys Ile Gly Pro Glu Thr Trp        Val                                                                           #   15                                                                        -      Cys Asp Trp Pro His Ile Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:107:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                               -      Gly Gly Pro Tyr Glu Gly Tyr Cys - # Ser Gly Gly Pro Val Thr Trp        Glu                                                                           #   15                                                                        -      Cys Cys Val Ser Val Cys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:108:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                               -      Gly Gly Gln Pro Leu Pro Tyr Cys - # Ser Pro Gly Pro Thr Thr Trp        Phe                                                                           #   15                                                                        -      Cys Ile Asn Trp Leu Phe Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:109:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                               -      Gly Gly Cys Ser Tyr Gly Tyr Cys - # Pro Met Gly Pro Phe Thr Trp        Met                                                                           #   15                                                                        -      Cys Arg Gln Arg Arg Leu Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:110:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                               -      Gly Gly Val Arg Gly Ser Tyr Cys - # Gln Ser Gly Pro Pro Thr Trp        Gln                                                                           #   15                                                                        -      Cys Asp Leu Arg Phe Phe Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:111:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                               -      Gly Gly Arg Cys Ala Arg Tyr Cys - # Ala Cys Gly Pro Gly Thr Trp        Asn                                                                           #   15                                                                        -      Cys Leu Gly Arg Cys Gln Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:112:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                               -      Gly Gly Leu Gly Arg Cys Tyr Cys - # Val Tyr Gly Pro Leu Thr Trp        Trp                                                                           #   15                                                                        -      Cys Ser Gln Thr Ser Leu Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:113:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                               -      Gly Gly Leu Cys Val Trp Tyr Cys - # Ser Ala Gly Pro Trp Thr Trp        Tyr                                                                           #   15                                                                        -      Cys Ile Tyr Arg Ser Ala Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:114:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                               -      Gly Gly Lys Pro Gly Pro Tyr Cys - # Ser Phe Gly Pro Glu Thr Trp        Val                                                                           #   15                                                                        -      Cys Thr Ala Leu Gly Met Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:115:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                               -      Gly Gly Arg Leu Gly Glu Tyr Cys - # Glu Ile Gly Pro Ile Thr Trp        Ile                                                                           #   15                                                                        -      Cys Arg Leu Phe Leu Pro Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:116:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                               -      Gly Gly Pro Gly Leu Gly Tyr Cys - # Asp Phe Gly Pro Leu Thr Trp        Val                                                                           #   15                                                                        -      Cys Asp Gly Ser Val Asp Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:117:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                               -      Gly Gly Leu Ser Ser Ala Tyr Cys - # Arg Tyr Gly Pro Glu Thr Trp        Ile                                                                           #   15                                                                        -      Cys Trp Ala Gly Thr Gly Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:118:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                               -      Gly Gly Val Leu His Leu Tyr Cys - # Tyr Tyr Gly Pro Glu Thr Trp        Asp                                                                           #   15                                                                        -      Cys Leu Pro Ile Lys Ala Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:119:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                               -      Gly Gly Gly Gly Gly Val Tyr Cys - # Leu Val Gly Pro Val Thr Trp        Leu                                                                           #   15                                                                        -      Cys Gly Pro Ala Ala Met Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:120:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                               -      Gly Gly Leu Thr Arg Asn Tyr Cys - # Arg Ile Gly Pro Glu Thr Trp        Ile                                                                           #   15                                                                        -      Cys Gln Glu Val Ala Ile Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:121:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                               -      Gly Gly Trp Ser Glu Arg Tyr Cys - # Val Leu Gly Pro Leu Thr Trp        Glu                                                                           #   15                                                                        -      Cys Val His Leu Phe Ala Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:122:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                               -      Gly Gly Met Pro Leu Lys Tyr Cys - # Gly Met Gly Pro Val Thr Trp        Val                                                                           #   15                                                                        -      Cys Cys Glu Ala Val Ser Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:123:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                               -      Gly Gly Ser Val Met Arg Tyr Cys - # His Phe Gly Pro Glu Thr Trp        Ile                                                                           #   15                                                                        -      Cys Pro Tyr Asp Met Pro Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:124:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                               -      Gly Gly Ala Leu Tyr Pro Tyr Cys - # Leu Ile Gly Pro Met Thr Trp        Val                                                                           #   15                                                                        -      Cys Gln Val Gly Trp Ile Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:125:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                               -      Gly Gly Thr Tyr Gly Asn Tyr Cys - # Arg Gly Gly Pro Gly Thr Trp        His                                                                           #   15                                                                        -      Cys Glu Asp Thr Arg Gly Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:126:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                               -      Gly Gly Ala Ser Tyr Cys Tyr Cys - # Ser Lys Gly Pro Ala Thr Trp        Lys                                                                           #   15                                                                        -      Cys Val Gly Ser Ile Leu Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:127:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                               -      Gly Gly Ser Leu Ala Ala Tyr Cys - # Leu Gln Gly Pro Lys Thr Trp        Pro                                                                           #   15                                                                        -      Cys Val Arg Arg Arg Leu Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:128:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 24 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                               -      Gly Gly Thr Asp Ser Leu Tyr Cys - # Lys Leu Gly Pro Leu Thr Trp        His                                                                           #   15                                                                        -      Cys Gln Leu Tyr Gln Lys Gly Gly                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:129:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 23 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                               -      Gly Ile Ser Gln Gln Tyr Cys Trp - # Arg Gly Pro Ala Thr Trp Val        Cys                                                                           #   15                                                                        -      Leu Glu Trp Glu Leu Gly Gly                                                             20                                                           - (2) INFORMATION FOR SEQ ID NO:130:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                               -      Arg Thr Lys Glu Tyr Ser Cys Gln - # Met Gly Pro Leu Thr Trp Ile        Cys                                                                           #   15                                                                        -      Val Pro Lys Ser                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:131:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                               -      Ser Lys Ala Arg Tyr Met Cys His - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Pro Glu Val                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:132:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                               -      Gly Gly Lys Ala Tyr Met Cys Arg - # Leu Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Ser Pro Arg Ile Lys Leu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:133:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                               -      Leu Leu Arg Gly Tyr Glu Cys Tyr - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Ser Ser Lys Pro Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:134:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                               -      Asn Gly Arg Thr Tyr Ser Cys Gln - # Leu Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Ser Arg Gly Val Arg Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:135:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                               -      Met Lys Thr Lys Tyr Lys Cys Tyr - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Glu Gly Ser                                                            - (2) INFORMATION FOR SEQ ID NO:136:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                               -      Ser Lys Thr Lys Tyr Arg Cys Glu - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Glu Arg Trp                                                            - (2) INFORMATION FOR SEQ ID NO:137:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                               -      Leu Thr Arg Leu Tyr Ser Cys His - # Met Gly Pro Ser Thr Trp Val        Cys                                                                           #   15                                                                        -      Ser Thr Ala Leu Arg Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:138:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                               -      Arg Gly Gln Leu Tyr Ala Cys His - # Phe Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Arg Arg Lys Arg Val                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:139:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                               -      Ser Gly Ile Leu Tyr Glu Cys His - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Thr Pro Ser Arg Arg Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:140:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                               -      Gly Ser Lys Thr Tyr Ser Cys Gln - # Leu Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Gly Arg Lys Arg                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:141:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                               -      Ala Arg Gly Lys Tyr Gln Cys Gln - # Phe Gly Pro Leu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Leu Pro Ile Arg Pro Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:142:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                               -      Val Thr Arg Met Tyr Arg Cys Arg - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Glu Arg                                                                - (2) INFORMATION FOR SEQ ID NO:143:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                               -      Lys Pro Ser Leu Tyr Glu Cys His - # Leu Gly Pro Leu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Arg Pro Arg Arg Arg Glu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:144:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                               -      Arg Gly His Met Tyr Ser Cys Gln - # Leu Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Leu Ser Gly Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:145:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 25 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                               -      Ile Thr Pro Thr Tyr His Cys Lys - # Phe Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Ala Pro Lys Arg Ser Ala Leu Thr - # Lys                                #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:146:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                               -      Gly Asn Arg Met Tyr Gln Cys His - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Gln Pro Thr Arg Ile His                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:147:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                               -      Met Lys Thr Lys Tyr Lys Cys Tyr - # Met Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Glu Gly Ser Arg Leu Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:148:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                               -      His Leu Gly Lys Tyr Asp Cys Ser - # Phe Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Arg Arg Ser Leu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:149:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                               -      Glu Arg Arg Val Tyr Glu Cys Gln - # Met Gly Pro Leu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Lys Pro Gly Val Lys Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:150:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                               -      Arg Gly Arg Gly Tyr Ser Cys Gln - # Met Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Arg Glu Arg Tyr Phe                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:151:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                               -      Arg Leu Arg Glu Tyr Arg Cys His - # Met Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Asn Gly His His Ser Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:152:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                               -      Ser Gly Ala Leu Tyr Asp Cys Gln - # Met Gly Pro Ile Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Ala Asn Arg Gln Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:153:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                               -      Thr Asn Gln Val Tyr Gly Cys Lys - # Phe Gly Pro Lys Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Ala Pro Arg Ile                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:154:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:154:                               -      Thr Arg Gly Met Tyr Ala Cys His - # Met Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Pro Thr Gln Pro Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:155:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:                               -      Val Leu Ser Asn Tyr Glu Cys Thr - # Met Gly Pro Lys Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Leu Arg Leu Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:156:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:156:                               -      Ala Leu Lys Lys Tyr Asp Cys Tyr - # Phe Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Leu Ala Arg Arg Pro His                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:157:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:157:                               -      Glu Arg Arg Phe Tyr Lys Cys Arg - # Phe Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Thr Leu                                                                - (2) INFORMATION FOR SEQ ID NO:158:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:158:                               -      Phe Gly Gln Glu Tyr Arg Cys His - # Leu Gly Pro Glu Thr Trp Gln        Cys                                                                           #   15                                                                        -      Ser Pro Val Arg Val Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:159:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:159:                               -      Phe Arg Pro Glu Tyr Met Cys Arg - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Gly Gly Ala Arg Pro                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:160:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:160:                               -      Gly Ser Arg Lys Tyr Trp Cys Arg - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Met Lys Pro Val Arg Leu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:161:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:161:                               -      Gly Leu Lys Ala Tyr Gly Cys Arg - # Tyr Gly Pro Glu Thr Trp Asp        Cys                                                                           #   15                                                                        -      Arg Ser Val Ile Leu Ile                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:162:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:162:                               -      Ile Arg Gln Pro Tyr Ile Cys His - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Gly Arg Tyr Pro Ala Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:163:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:163:                               -      Lys Gly Ala Ser Tyr His Cys Ile - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Ile Pro Gln Arg Val Trp                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:164:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:164:                               -      Met Lys Gln Leu Tyr Ser Cys Ile - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Arg Pro Gly Val Glu Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:165:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:165:                               -      Gln Arg His Tyr Tyr Arg Cys Ala - # Leu Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Arg Pro Met Ser Pro Glu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:166:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:166:                               -      Thr Lys Arg Leu Tyr His Cys His - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      His Gly Pro Met Arg Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:167:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:167:                               -      Thr Arg Pro Ser Tyr Arg Cys Ala - # Phe Gly Pro Val Thr Trp Glu        Cys                                                                           #   15                                                                        -      Ile Pro Ala Arg                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:168:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:168:                               -      Arg His Lys Ser Tyr Val Cys Thr - # Phe Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Thr Gly Ala Ile Arg Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:169:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:169:                               -      Arg Gly Arg Met Tyr Asn Cys Arg - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Lys Gly Gln Ser Lys Asp                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:170:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:                               -      Arg Arg Arg Tyr Tyr Arg Cys Trp - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Ser Pro Val Ser Asn Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:171:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:171:                               -      Val Ala Asp Asn Tyr Asp Cys Pro - # Ile Gly Pro Val Thr Trp Glu        Cys                                                                           #   15                                                                        -      Ile His Val Arg Ala Ser                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:172:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:172:                               -      Val Gln Lys Lys Tyr Leu Cys His - # Phe Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Gly Pro Asp Arg Asp                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:173:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:173:                               -      Trp Gln Thr Trp Tyr Ile Cys Glu - # Arg Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Arg Trp Leu Val Leu                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:174:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:174:                               -      Tyr Arg Met Pro Tyr Arg Cys Lys - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Val Gly Gly Arg Gly Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:175:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:175:                               -      Tyr Ser Arg Glu Tyr Ser Cys Arg - # Met Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Xaa Arg Gly Phe Leu Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:176:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176:                               -      Arg Ser Met Trp Tyr Arg Cys Gln - # Met Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Gly Pro Arg Ser Ala Ser                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:177:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:177:                               -      Ser Arg Arg Glu Tyr Ile Cys His - # Leu Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Gly Pro Gly Gly Arg Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:178:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:178:                               -      Gly Ser Pro Ser Tyr His Cys His - # Leu Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro His Arg Met Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:179:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 21 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:179:                               -      Met Val Gly Arg Tyr Gln Cys His - # Met Gly Pro Arg Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Trp His Gly                                                                     20                                                           - (2) INFORMATION FOR SEQ ID NO:180:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:180:                               -      Gly Thr Ala Arg Tyr Gln Cys His - # Phe Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Ser Leu Lys Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:181:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:181:                               -      Glu Leu Arg Gly Tyr Ile Cys His - # Phe Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Pro Asn Gly Ser Arg                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:182:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:182:                               -      Leu Lys Gln Gly Tyr Gln Cys Gln - # Leu Gly Pro Gln Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Pro Leu Arg Met Pro                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:183:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:183:                               -      Lys Glu Arg Lys Tyr Glu Cys Gln - # Phe Gly Pro Arg Thr Trp Val        Cys                                                                           #   15                                                                        -      Gln Pro Thr Arg Ala Asn                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:184:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:184:                               -      Val Arg Lys Val Tyr Ala Cys His - # Met Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Val Pro Gly Tyr Lys Gly                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:185:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:185:                               -      Ser Gly Gln Arg Tyr Val Cys Arg - # Met Gly Pro Glu Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Ser Tyr Arg Gly Leu                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:186:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:186:                               -      Glu Arg Arg Ser Tyr Ser Cys Gln - # Met Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Gly Arg Gln Met Gly Gln                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:187:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:                               -      Val Lys Asn Asn Tyr Arg Cys Gln - # Phe Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Lys Ala Phe Arg                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:188:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:188:                               -      Ser Gly Ala Ser Tyr Asp Cys Gln - # Met Gly Pro Ile Thr Trp Val        Cys                                                                           #   15                                                                        -      Arg Ala Asn Arg Gln Lys                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:189:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:189:                               -      Gly Gly Thr Thr Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:190:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:190:                               -      Gly Gly Thr Phe Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:191:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:191:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Ala Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:192:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:192:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Ala Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:193:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:193:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Ala Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:194:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:194:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Ala Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:195:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:195:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Ala Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:196:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:196:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Phe Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:197:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:197:                               -      Thr Tyr Ser Cys His Phe Gly Pro - # Leu Thr Trp Val Cys Lys Pro        Gln                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:198:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:198:                               -      Tyr Ser Cys His Phe Gly Pro Leu - # Thr Trp Val Cys Lys Pro            #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:199:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:199:                               -      Tyr Ser Cys His Phe Gly Ala Leu - # Thr Trp Val Cys Lys                #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:200:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:200:                               -      Ser Cys His Phe Gly Pro Leu Thr - # Trp Val Cys Lys                    #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:201:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:201:                               -      His Phe Gly Pro Leu Thr Trp Val                                        #  5 1                                                                        - (2) INFORMATION FOR SEQ ID NO:202:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: circular                                              -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Cross-links                                                     (B) LOCATION: 6..16                                                 #/product= "OTHER"R INFORMATION:                                              #"An amide bond joins the                                                                    delta car - #boxyl group of Glu at                             #6 to the epsilon amine group                                                 #at position 16"f Lys                                                         -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:202:                               -      Gly Gly Thr Tyr Ser Glu His Phe - # Gly Pro Leu Thr Trp Val Lys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:203:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:203:                               -      Gly Gly Thr Tyr Arg Cys Ser Met - # Gly Pro Met Thr Trp Val Cys        Leu                                                                           #   15                                                                        -      Pro Met Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:204:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:204:                               -      Gly Gly Met Tyr Ser Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Gly                                                                           #   15                                                                        -      Pro Ser Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:205:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:205:                               -      Gly Gly Trp Ala Trp Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Ala His Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:206:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:206:                               -      Gly Gly Met Tyr Ser Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Ile                                                                           #   15                                                                        -      Pro Tyr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:207:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:207:                               -      Gly Gly Asp Tyr Thr Cys Arg Met - # Gly Pro Met Thr Trp Ile Cys        Thr                                                                           #   15                                                                        -      Ala Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:208:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:208:                               -      Gly Gly Asn Tyr Leu Cys Arg Phe - # Gly Pro Gly Thr Trp Asp Cys        Thr                                                                           #   15                                                                        -      Gly Phe Arg Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:209:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:209:                               -      Gly Gly Lys Asp Val Cys Arg Met - # Gly Pro Ile Thr Trp Asp Cys        Arg                                                                           #   15                                                                        -      Ser Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:210:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:210:                               -      Gly Gly Asn Tyr Leu Cys Arg Met - # Gly Pro Ala Thr Trp Val Cys        Gly                                                                           #   15                                                                        -      Arg Met Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:211:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:211:                               -      Gly Gly Glu Tyr Lys Cys Arg Met - # Gly Pro Leu Thr Trp Val Cys        Gln                                                                           #   15                                                                        -      Tyr Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:212:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:212:                               -      Gly Gly Val Tyr Val Cys Arg Met - # Gly Pro Leu Thr Trp Glu Cys        Thr                                                                           #   15                                                                        -      Ala Ser Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:213:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:213:                               -      Gly Gly Glu Tyr Ser Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:214:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:214:                               -      Gly Gly Asn Tyr Ile Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Ala His Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:215:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:215:                               -      Gly Gly Asp Tyr Leu Cys Arg Met - # Gly Pro Ala Thr Trp Val Cys        Gly                                                                           #   15                                                                        -      Arg Met Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:216:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:216:                               -      Gly Gly Leu Tyr Ser Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Lys Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:217:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:217:                               -      Gly Gly Gly Tyr His Cys Arg Met - # Gly Pro Met Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:218:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:218:                               -      Gly Gly Leu Tyr Ser Cys Leu Met - # Gly Pro Ile Thr Trp Leu Cys        Lys                                                                           #   15                                                                        -      Pro Lys Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:219:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:219:                               -      Gly Gly Asp Tyr Ser Cys Arg Met - # Gly Pro Thr Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Pro Pro Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:220:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:220:                               -      Gly Gly Asp Tyr Trp Cys Arg Met - # Gly Pro Ser Thr Trp Glu Cys        Asn                                                                           #   15                                                                        -      Ala His Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:221:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:221:                               -      Gly Gly Lys Tyr Leu Cys Ser Phe - # Gly Pro Ile Thr Trp Val Cys        Ala                                                                           #   15                                                                        -      Arg Tyr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:222:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:222:                               -      Gly Gly Leu Tyr Lys Cys Arg Leu - # Gly Pro Ile Thr Trp Val Cys        Ser                                                                           #   15                                                                        -      Pro Leu Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:223:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:223:                               -      Gly Gly Ser Tyr Thr Cys Arg Phe - # Gly Pro Glu Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Asn Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:224:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:224:                               -      Gly Gly Ser Tyr Ser Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gly Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:225:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:225:                               -      Gly Gly Ser Tyr Thr Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Leu                                                                           #   15                                                                        -      Pro Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:226:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:226:                               -      Gly Gly Asp Tyr Thr Cys Arg Met - # Gly Pro Ile Thr Trp Ile Cys        Thr                                                                           #   15                                                                        -      Lys Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:227:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:227:                               -      Gly Gly Val Tyr Ser Cys Arg Met - # Gly Pro Thr Thr Trp Glu Cys        Asn                                                                           #   15                                                                        -      Arg Tyr Val Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:228:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:228:                               -      Gly Gly Ala Tyr Leu Cys His Met - # Gly Pro Ile Thr Trp Val Cys        Arg                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:229:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:229:                               -      Gly Gly Glu Tyr Ser Cys Arg Met - # Gly Pro Asn Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Val Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:230:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:230:                               -      Gly Gly Leu Tyr Thr Cys Arg Met - # Gly Pro Ile Thr Trp Val Cys        Leu                                                                           #   15                                                                        -      Leu Pro Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:231:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:231:                               -      Gly Gly Leu Tyr Thr Cys Arg Met - # Gly Pro Val Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Gly Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:232:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:232:                               -      Gly Gly Val Tyr Lys Cys Arg Met - # Gly Pro Leu Thr Trp Glu Cys        Arg                                                                           #   15                                                                        -      Pro Thr Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:233:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:233:                               -      Gly Gly Ser Tyr Leu Cys Arg Phe - # Gly Pro Thr Thr Trp Leu Cys        Ser                                                                           #   15                                                                        -      Ser Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:234:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:234:                               -      Gly Gly Ser Tyr Leu Cys Arg Met - # Gly Pro Thr Thr Trp Val Cys        Thr                                                                           #   15                                                                        -      Arg Met Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:235:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:235:                               -      Gly Gly Ser Tyr Leu Cys Arg Phe - # Gly Pro Thr Thr Trp Leu Cys        Thr                                                                           #   15                                                                        -      Gln Arg Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:236:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:236:                               -      Gly Gly Gln Tyr Leu Cys Thr Phe - # Gly Pro Ile Thr Trp Leu Cys        Arg                                                                           #   15                                                                        -      Gly Ala Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:237:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:237:                               -      Arg Ile Gly Pro Ile Thr Trp Val                                        #  5 1                                                                        - (2) INFORMATION FOR SEQ ID NO:238:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #pairs    (A) LENGTH: 94 base                                                           (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: DNA                                                 -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:238:                               - CTCTCACTCC GGAGGCNNKN NKNNKTGTCG KATKGGKCCK ATKACKTGKG TK - #TGTNNKNN         60                                                                          #        94        AGCA CTGTTGAAAG TTGT                                       - (2) INFORMATION FOR SEQ ID NO:239:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 29 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:239:                               -      Gly Gly Xaa Xaa Xaa Xaa Tyr Xaa - # Cys Arg Ile Gly Pro Ile Thr        Trp                                                                           #   15                                                                        -      Val Cys Xaa Xaa Xaa Xaa Xaa Xaa - # Gly Gly Gly Gly Ser                #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:240:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:240:                               -      Gly Gly Gly Ser                                                             1                                                                        - (2) INFORMATION FOR SEQ ID NO:241:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = unsure amino acid"                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:241:                               -      Gly Gly Tyr Gln Xaa Phe Met Gly - # Pro Glu Thr Trp Val Cys Ala        Pro                                                                           #   15                                                                        -      Glu Pro Arg Val Glu Arg Val Ser - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:242:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 26 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:242:                               -      Gly Gly Tyr Leu Cys Arg Phe Gly - # Pro Glu Thr Trp Thr Cys Ala        Pro                                                                           #   15                                                                        -      Glu Arg Ser Val Val Thr Gln Ser - # Gly Gly                            #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:243:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:243:                               -      Leu Gly Arg Lys Tyr Ser Cys His - # Phe Gly Pro Val Thr Trp Val        Cys                                                                           #   15                                                                        -      Gln Pro Ala Lys Lys Asp                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:244:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 19 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:244:                               -      Gly Gly Thr Tyr Ser Cys Phe Gly - # Pro Leu Thr Trp Val Cys Lys        Pro                                                                           #   15                                                                        -      Gln Gly Gly                                                            - (2) INFORMATION FOR SEQ ID NO:245:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:245:                               -      Thr Tyr Ser Cys His Phe Gly Pro - # Leu Thr Trp Val Cys Lys Pro        Gln                                                                           #   15                                                                        -      Gly Gly                                                                - (2) INFORMATION FOR SEQ ID NO:246:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:246:                               -      Tyr Ser Cys His Phe Gly Pro Leu - # Thr Trp Val Cys                    #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:247:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/product= "OTHER"R INFORMATION:                                              #"Xaa = para-nitro-phenylalanine"                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:247:                               -      Gly Gly Thr Xaa Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:248:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/product= "OTHER"R INFORMATION:                                              #"Xaa = para-amino-phenylalanine"                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:248:                               -      Gly Gly Thr Xaa Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:249:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/product= "OTHER"R INFORMATION:                                              #"Xaa = para-fluoro-phenylalanine"                                            -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:249:                               -      Gly Gly Thr Xaa Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:250:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/product= "OTHER"R INFORMATION:                                              #"Xaa = 3,5-dibromo-tyrosine"                                                 -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:250:                               -      Gly Gly Thr Xaa Ser Cys His Phe - # Gly Pro Leu Thr Trp Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:251:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 20 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:251:                               -      Gly Gly Thr Tyr Ser Cys His Phe - # Gly Pro Leu Thr Phe Val Cys        Lys                                                                           #   15                                                                        -      Pro Gln Gly Gly                                                                         20                                                           - (2) INFORMATION FOR SEQ ID NO:252:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa = Arg, His, or Leu"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:252:                               -      Cys Xaa Xaa Gly Pro Xaa Thr Trp - # Xaa Cys                            #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:253:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa = Arg, His, or Leu"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 11                                                    #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:253:                               -      Tyr Xaa Cys Xaa Xaa Gly Pro Xaa - # Thr Trp Xaa Cys                    #   10                                                                        - (2) INFORMATION FOR SEQ ID NO:254:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa = Arg, His, or Leu"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa = Met, Phe, or Ile"                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 12                                                    #/note= "Xaa = Asp, Glu, Ile, Leu,                                                           or Val"                                                        -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 14                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 15                                                    #/note= "Xaa = any amino acid"N:                                              -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 16                                                    #/note= "Xaa = any amino acid"N:                                              -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:254:                               -      Xaa Tyr Xaa Cys Xaa Xaa Gly Pro - # Xaa Thr Trp Xaa Cys Xaa Xaa        Xaa                                                                           #   15                                                                        - (2) INFORMATION FOR SEQ ID NO:255:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 27 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:255:                               -      Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa - # Xaa Xaa Tyr Xaa Cys Xaa Xaa        Gly                                                                           #   15                                                                        -      Pro Xaa Thr Trp Xaa Cys Gly Gly - # Gly Gly Ser                        #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:256:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 27 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:256:                               -      Gly Gly Xaa Xaa Xaa Xaa Tyr Cys - # Xaa Xaa Gly Pro Xaa Thr Trp        Xaa                                                                           #   15                                                                        -      Cys Xaa Xaa Xaa Xaa Xaa Gly Gly - # Gly Gly Ser                        #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:257:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 29 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:257:                               -      Gly Gly Tyr Xaa Cys Xaa Xaa Gly - # Pro Xaa Thr Trp Xaa Cys Xaa        Xaa                                                                           #   15                                                                        -      Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa - # Gly Gly Gly Gly Ser                #                 25                                                          - (2) INFORMATION FOR SEQ ID NO:258:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:258:                               -      Xaa Xaa Xaa Xaa Tyr Xaa Cys His - # Phe Gly Pro Leu Thr Trp Val        Cys                                                                           #   15                                                                        -      Xaa Xaa Xaa Xaa Xaa Xaa                                                                 20                                                           - (2) INFORMATION FOR SEQ ID NO:259:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 22 amino                                                          (B) TYPE: amino acid                                                          (C) STRANDEDNESS:                                                             (D) TOPOLOGY: linear                                                -     (ii) MOLECULE TYPE: peptide                                             -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:259:                               -      Xaa Xaa Xaa Xaa Tyr Xaa Cys Xaa - # Xaa Gly Pro Glu Thr Trp Glu        Cys                                                                           #   15                                                                        -      Xaa Xaa Xaa Xaa Xaa Xaa                                                                 20                                                           __________________________________________________________________________

What is claimed:
 1. A peptide dimer comprising two monomeric peptides of10 to about 40 amino acids in length that bind to erythropoietinreceptor, each monomeric peptide comprising a sequence of amino acidsX₃X₄ X₅ GPX₆ TWX₇ X₈ (SEQ ID NO:252)where each amino acid is indicated bystandard one letter abbreviation; X₆ is independently selected from anyone of the 20 genetically coded L-amino acids; X₃ is C; X₄ is R, H, L,or W; X₅ is M, F, or I; X₇ is D, E, I, L, or V; and X₈ is C.
 2. Thepeptide dimer of claim 1, wherein each of said monomeric peptidescomprises a sequence of amino acidsYX₂ X₃ X₄ X₅ GPX₆ TWX₇ X₈ (SEQ IDNO:253)where each amino add is indicated by standard one letterabbreviation; each of X₂ and X₆ is independently selected from any oneof the 20 genetically coded L-amino acids; X₃ is C; X₄ is R, H, L, or W;X₅ is M, F, or I; X₇ is D, E, I, L, or V; and X₈ is C.
 3. The peptidedimer of Claim 2, wherein each of said monomeric peptides comprises asequence of amino acidsX₁ YX₂ X₃ X₄ X₅ GPX₆ TWX₇ X₈ X₉ X₁₀ X₁₁ (SEQ IDNO:254)where each amino acid is indicated by standard one letterabbreviation; each of X₁, X₂, X₆, X₉, X₁₀, and X₁₁ is independentlyselected from any one of the 20 genetically coded L-amino acids; X₃ isC; X₄ is R, H, L, or W; X₅ is M, F, or I; X₇ is D, E, I, L, or V, and X₈is C.
 4. The peptide dimer of claim 3 wherein X₄ is R or H; X₅ is F orM; X₆ is I, L, T, M, or V; X₇ is D or V; X₉ is G K, L, Q, R, S, or T;and X₁₀ is A, G, P, R, or Y.
 5. The peptide dimer of Claim 4, wherein X₁is D, E, L, N, S, T, or V; X₂ is A, H, K, L, M, S, or T; X₄ is R or H;X₉ is K, R, S, or T; and X₁₀ is P.
 6. The peptide dimer of claim 5,wherein each of said monomeric peptides is GGTYSCHFGPLTWVCKPQGG (SEQ IDNO:8).
 7. The peptide dimer of any one of claims 1-6, wherein theC-terminus of one of said monomeric peptides is covalently bound to theN-terminus of the other monomeric peptide.
 8. The peptide dimer of anyone of claims 1-6, wherein the N-terminus of one of said monomericpeptides is covalently bound to the N-terminus of the other monomericpeptide.
 9. The peptide dimer of any one of claims 1-6, wherein thecysteine residue of one of said monomeric peptides is covalently boundto the cysteine residue of the other monomeric peptide.